Prostaglandin Analog Compositions To Treat Epithelial-Related Conditions

ABSTRACT

The present invention relates to the formulation and delivery of prostaglandin analogs to treat epithelial-related condition. In some embodiments, the compositions of the invention are used to stimulate hair growth. In some embodiments, the compositions of the invention are used to restore hair color to depigmented hair.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/984,198, filed Oct. 31, 2007, the contents of which are incorporatedby reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to the formulation and delivery ofprostaglandin analogs to treat epithelial-related conditions. In someembodiments, the compositions of the invention are used to stimulatehair growth. In some embodiments, the compositions of the invention areused to restore hair color to depigmented hair.

BACKGROUND OF THE INVENTION

Hair, a filamentous outgrowth of protein found only on mammals, isintegral to our body image and can have a profound influence on ourself-esteem and self-confidence. The hair of non-human mammal species iscommonly referred to as fur. In some species, hair is absent at certainstages of life.

Hair grows from hair follicles deep in the dermis and projects from theepidermis of the skin. Human skin has two types of hair: vellus hair andterminal hair. Much of human hair is short, underpigmented vellus hairrather than terminal hair. The most noticeable part of human hair is thehair on the head, which can grow longer than on most mammals and is moredense than most hair found elsewhere on the body. The term “scalp”refers to the integument of the upper part of the head, usuallyincluding the associated subcutaneous structures. The scalp is theanatomical area bordered by the face anteriorly and the neck to thesides and posteriorly.

Vellus hair is short, fine, “peach fuzz” body hair. It is a very soft,generally pale, and short hair that grows in most places on the humanbody in both sexes. It is usually less than two cm long and thefollicles are not connected to sebaceous glands. It is most easilyobserved in women and children, as they have less terminal hair toobscure it. It is also found in pre-adolescents and in male patternbaldness.

Terminal hair is developed hair, which is generally longer, coarser,thicker and darker than the shorter and finer vellus hair. Phases ofgrowth in terminal hair are more apparent than in vellus hair; itgenerally has a longer anagen phase. It has associated sebaceous glands,whereas a vellus hair may not. Under certain conditions, such aspuberty, some vellus hair may become androgenic hair. Under otherconditions, such as male pattern baldness, it may revert to avellus-like state.

Each hair comprises two structures: the follicle in the skin and theshaft we see. The follicle contains several layers. At the base of thefollicle is a projection called a papilla, which contains capillaries,or tiny blood vessels, that feed the cells. The living part of the hair,the area surrounding the papilla called the bulb, is the only part fedby the capillaries. The cells in the bulb divide every 23 to 72 hours,faster than any other cells in the body. The follicle is surrounded bytwo sheaths—an inner and outer sheath. These sheaths protect and moldthe growing hair shaft. The inner sheath follows the hair shaft and endsbelow the opening of a sebaceous (oil) gland, which produces sebum, anatural conditioner and sometimes an apocrine (scent) gland. The outersheath continues all the way up to the gland. An erector pili muscleattaches below the gland to a fibrous layer around the outer sheath.When this muscle contracts, it causes the hair to stand up.

The primary component of the hair fiber is keratin. Keratins areproteins, long chains (polymers) of amino acids. The hair shaft containsthree layers of keratin. The inner layer, which is called the medulla,may not be present. The next layer is the cortex, which makes up themajority of the hair shaft. The outer layer is the cuticle, which isformed by tightly packed scales in an overlapping structure similar toroof shingles. Most hair conditioning products attempt to affect thecuticle. Pigment cells are distributed throughout the cortex and medullagiving the hair its characteristic color.

The term “eyebrow” refers to an area of coarse skin hairs above the eyethat follows the shape of the brow ridges. The main function of theeyebrow is to prevent moisture, mostly salty sweat and rain, fromflowing into the eye, an organ critical to sight. The typical curvedshape of the eyebrow (with a slant on the side) and the direction inwhich eyebrow hairs are pointed, make sure that moisture has a tendencyto flow sideways around the eyes, along the side of the head and alongthe nose. Eyebrows also prevent debris such as dandruff and other smallobjects from falling into the eyes, as well as providing a moresensitive sense for detecting objects being near the eye, like smallinsects. Eyebrows also have an important facilitative function incommunication, strengthening facial expressions such as surprise,confusion, or anger.

The terms “eyelash” and “lash” are used interchangeably to refer to oneof the hairs that grow at the edge of the eyelid. Eyelashes protect theeye from debris and provide a warning that an object (such as an insector dust mite) is near the eye (which then is closed reflexively).

The inside of the nose contains small hairs called cilia. These ciliaand nasal mucus clean the air drawn into the nose of the microscopicparticles we inhale, including dust, pollen, and pollutants, forultimate passage to the lungs.

Hair Biology

There are three stages of hair growth: catagen, telogen, and anagen.

Anagen is the active growth phase of the hair during which the cells inthe root of the hair are dividing rapidly. Anagen hairs are anchoreddeeply into the subcutaneous fat and cannot be pulled out easily. When anew hair is formed, it pushes the club hair up the follicle andeventually out. During this phase the hair grows about 1 cm every 28days. Scalp hair stays in this active phase of growth for 2-6 years.Human subjects that have difficulty growing their hair beyond a certainlength have a short active phase of growth. Human subjects that havevery long hair have a long active phase of growth. The hair on the arms,legs, eyelashes, and eyebrows have a very short active growth phase ofabout 30-45 days, which is why they are so much shorter than scalp hair.

The anagen phase is followed by a catagen phase. The catagen phase is atransitional stage that lasts for about 2-3 weeks. About 3% of all hairsare in this phase at any time. During this time growth stops and theouter root sheath shrinks and attaches to the root of the hair. This isthe formation of what is known as a club hair.

After catagen, the hair goes into a telogen phase. Telogen is theresting phase, which accounts for 10-15% of all hairs. It lasts forabout 100 days for hairs on the scalp and much longer for hairs on theeyebrow, eyelash, arm and leg. During this phase the hair follicle iscompletely at rest and the club hair is completely formed. As comparedwith anagen hair, telogen hair is located higher in the skin and can bepulled out relatively easily. Pulling out a hair in this phase willreveal a solid, hard, dry, white material at the root. Normally, about25-100 telogen hairs are shed each day.

In the normal scalp, approximately 80 to 90 percent of follicles aregrowing (anagen), about 5 to 10 percent are resting (telogen), and 1 to3 percent are undergoing involution (catagen). Each day up to 75 hairsin telogen are shed from the scalp and about the same number offollicles enter anagen.

The term “alopecia” is a medical term for the absence or loss of hairincluding eyelashes, eyebrows, and scalp hair, as a result of illness,functional disorder, or hereditary disposition. For example, the term“Alopecia adnata” refers to underdevelopment of the eyelashes. Alopeciafrequently occurs in patients undergoing treatment for cancer orsuffering from other diseases, such as AIDS, where cell-killing, orcytotoxic, drugs are used.

Hair loss typically is categorized as scarring or nonscarring. Scarringalopecia, also known as “cicatricial alopecia”, refers to a collectionof hair loss disorders that may be diagnosed in up to 3% of hair losspatients. It occurs worldwide in otherwise healthy men and women of allages. While there are many forms of scarring alopecia, the common themeis a potentially permanent and irreversible destruction of hairfollicles and their replacement with scar tissue. Examples includebullous diseases, chemical alopecia, discoid lupus erythematosus,folliculitis (severe), lichen planopilaris, dissecting cellulitis, andtumors.

The term “nonscarring alopecia” refers to hair loss without permanentdestruction of the hair follicle. Examples include anagen effluvium,androgenetic alopecia, chemical alopecia, folliculitis (mild), inheriteddisorders of the hair shaft, telogen effluvium, alopecia areata, andtraumatic alopecia.

The term “anagen effluvium” refers to the hair loss associated withchemotherapeutic agents that cause immediate destruction and release ofanagen hair.

The term “androgenic alopecia” refers to a gradual decrease of scalphair density in adults with transformation of terminal to vellus hairs,which become lost as a result of familial increased susceptibility ofhair follicles to androgen secretion following puberty. The most commonform of androgenic alopecia is male pattern baldness. The most commonform of androgenic alopecia in women is female pattern alopecia, adiffuse partial hair loss in the centroparietal area of the scalp, withpreservation of the frontal and temporal hairlines. When it occurs infemales, it is associated with other evidence of excessive androgenactivity, such as hirsutism.

The term “telogen effluvium” refers to a condition resulting from anabrupt shift of large numbers of anagen hairs to telogen hairs on thescalp, with a corresponding change in the ratio of anagen hair totelogen hair from the normal ratio of 90:10 to 70:30. This form ofalopecia generally begins approximately 3 months after a major illnessor other stress (e.g., surgery, parturition, rapid weight loss,nutritional deficiency, high fever, or hemorrhage) or hormonalderangement; it also has been reported after the initiation of treatmentwith certain medications.

The term “alopecia areata” refers to a common condition of undeterminedetiology characterized by circumscribed, nonscarring, usuallyasymmetrical areas of baldness on the scalp, eyebrows, and beadedportion of the face. Hairy skin anywhere on the body may be affected. Itis thought to be an autoimmune disease occurring on areas of the body(most commonly the scalp) where the person's immune system attacks hairfollicles, thereby suppressing and arresting hair growth.

Those suffering from hair loss often experience embarrassment and thefear being ridiculed by others because they look different. Some maytake to wearing oversized eyeglasses in an attempt to hide the absenceof eyelashes and/or eyebrows. Loss of nasal cilia may render some moresusceptible to respiratory illnesses.

Current therapies for hair loss are designed primarily for scalpapplications. These include topical minoxidil (Rogain®), antiandrogenagents, including the androgen-receptor blockers spironolactone,cyproterone acetate, and flutamide, and the 5α-reductase inhibitorfinasteride (Propecia®, Merck & Co.), preparations of progesteroneand/or estrogen, and hair transplantation.

Prostaglandins are a family of a group of lipid compounds that arederived enzymatically in the body from essential fatty acids. Everyprostaglandin contains 20 carbon atoms, including a 5-carbon ring.Prostaglandins have a wide variety of effects, including, but notlimited to, muscular constriction, mediating inflammation, calciummovement, hormone regulation and cell growth control. Prostaglandins acton a variety of cells, including vascular smooth muscle cells (causingconstriction or dilation), platelets (causing aggregation ordisaggregation), and spinal neurons (causing pain).

Scientists stumbled on the hair thickening properties of prostaglandinF_(2α) analogs while researching their use as an intraocular pressure(IOP)-lowering drug for use in patients with glaucoma and ocularhypertension. Prostaglandin F_(2 α) analogs have the following generalchemical structure wherein the dashed bonds represent a single or doublebond which can be in the cis or trans configuration:

For example, latanoprost[(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate],marketed by Pfizer as Xalatan® is a prostaglandin analog in which R isH, B is —CH₂—, n is 0, X is OCH(CH₃)₂, and the dashed bonds represent adouble bond. See U.S. Pat. No. 6,262,105, issued to Johnstone. AlthoughJohnstone reported the stimulating effect of this drug on eyebrow andeyelash hair growth and pigmentation, Latanoprost works poorly oneyelashes.

Another example, is bimatoprost (cyclopentane N-ethylheptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,4-dihydroxy,[1_(α), 2_(β), 3_(α), 5_(α)], sold by Allergan, Inc. of Irvine, Calif.as Lumigan®, a 0.03% ophthalmic solution for treating glaucoma.Bimatoprost is a prostaglandin analog in which R is H, B is —CH₂—, n is0, X is NHC₂H₅ and the dashed bonds represent a double bond (U.S.Published Application No. 2003/0147823). Bimatoprost, which also hasbeen found effective to increase the growth of eyelashes when applied inthe FDA approved manner, dissolves best for use on eyelashes but hasnegative side effects, such as, for example, redness and discolorationalong the periocular skin; eye irritation; and foreign body sensation.In addition, bimtoprost has the highest incidence of hyperemia.

Another synthetic prostaglandin analog used for treatment of glaucoma isisopropyl(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3R)-3-hydroxy-4-[(α,α,α-trifluoro-m-tolyl)oxy]-1-butenyl]cyclopentyl]-5-heptenoate,or Travaprost (TRAVATAN® Alcon), which is available as a 0.004%ophthalmic solution. Travoprost is a prostaglandin analog in which R isH, B is O, Y is CF₃, X is OCH(CH₃)₂, and the dashed bonds represent adouble bond. Travaprost does not work well for eyelash growth, takinglonger than other like products.

Therefore it is an object of the present invention to provideprostaglandin analogs that will promote appropriate hair growth whenapplied topically to subjects in need thereof without causingsignificant undesirable side effects.

SUMMARY OF THE INVENTION

The present invention relates to the formulation and delivery ofprostaglandin analogs to treat an epithelial-related condition. In someembodiments, the compositions of the invention are used to stimulatehair growth. In some embodiments, the compositions of the invention areused to restore hair color to depigmented hair. According to one aspect,the present invention provides a topical composition for treating anepithelial-related condition, comprising (a) at least one compound offormula XII or a salt of formula XII:

wherein the simple straight line represents a bond lying approximatelyin the surface plane; the wedge shaped bond is directed to the front ofsurface plane; and the hatched bond is directed in the back of thesurface plane; and wherein the compound has optically active isomerswhenever chiral centers are present; and (b) a carrier, whereby thecomposition stimulates hair growth on an epithelial surface to which thecomposition has been applied. According to one embodiment, the at leastone compound of formula XII is (16-(3-chlorophenoxy)-17, 18, 19,20-tetranor PGF_(2α)) cyclopropyl methyl amide. According to anotherembodiment, the composition is an ophthalmic composition. According toanother embodiment, the composition restores pigmentation to depigmentedhair. According to another embodiment, the epithelial-related conditionis alopecia. According to another embodiment, the epithelial surfaceonto which the composition is applied topically is an eyelid. Accordingto another embodiment, the epithelial-related condition is alopeica ofat least one eyelash. According to another embodiment, the epithelialsurface onto which the composition is applied topically is a face.According to another embodiment, the condition is alopecia of at leastone eyebrow. According to another embodiment, the epithelial surfaceonto which the composition is applied topically is above a lip.According to another embodiment, the compound of (a) is present in apharmaceutically effective amount. According to another embodiment, thecompound of (a) is present in a cosmetically effective amount. Accordingto another embodiment, the compound of (a) is present in acosmeceutically effective amount.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to synthetic analogs of prostaglandinF_(2α).

“Aliphatic” as used herein, denotes a straight- or branched-chainarrangement of constituent carbon atoms, including, but not limited toparaffins (alkanes), which are saturated, olefins (alkenes oralkadienes), which are unsaturated, and acetylenes (alkynes), whichcontain a triple bond. In complex structures, the chains may be branchedor cross-linked.

“Alkyl,” as used herein, denotes a straight (unbranched) or branchedunivalent aliphatic group of about 1 to about 25 carbon atoms including,e.g., methyl, ethyl, propyl, isopropyl, decyl, undecyl, dodecyl,octadecyl, nonadecyl, eicosyl, heneicosyl, decosyl, tricosyl,tetracosyl, and pentacosyl, and the branched (non-straight-chained)isomers thereof, with multiple degrees of substitution being allowed. Insome embodiments of the present invention, the prostaglandin analog hasan alkyl of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms.

“Alkenyl,” as used herein, denotes a monovalent, straight (unbranched)or branched hydrocarbon chain having one or more double bonds thereinwhere the double bond can be unconjugated or conjugated to anotherunsaturated group (e.g., a polyunsaturated alkenyl) and can beunsubstituted or substituted, with multiple degrees of substitutionbeing allowed. For example, and without limitation, the alkenyl can bevinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl,hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl,4-(2-methyl-3-butene)-pentenyl, decenyl, undecenyl, dodecenyl,heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl,docosenyl, tricosenyl, tetracisenyl, pentacosenyl, phytyl, the branchedchain isomers thereof, and polyunsaturated alkenes includingoctadec-9,12,-dienyl, octadec-9,12,15-trienyl, andeicos-5,8,11,14-tetraenyl.

As used herein, the term “aryl” refers to a benzene ring or to anoptionally substituted benzene ring system fused to one or moreoptionally substituted benzene rings, with multiple degrees ofsubstitution being allowed. Examples of aryl include, but are notlimited to, phenyl, 2-napthyl, 1-naphthyl, 1-anthracenyl, and the like.

It should be understood that wherever the terms “alkyl” or “aryl” oreither of their prefix roots appear in a name of a substituent, they areto be interpreted as including those limitations given above for alkyland aryl.

As used herein, the terms “carbamates” or “urethanes” refer to a groupof organic compounds sharing a common functional group having thegeneral structure —NH(CO)O—.

As used herein, the terms “cycloalkyl” or “aliphatic cyclic” are usedinterchangeably to refer to an alicyclic hydrocarbon group optionallypossessing one or more degrees of unsaturation, having from three totwelve carbon atoms, optionally substituted with substituents, withmultiple degrees of substitution being allowed. “Cycloalkyl” includes,but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, and the like.

As used herein, the terms “heterocycle” and “heterocyclic” are usedinterchangeably to refer to a three to twelve-membered heterocyclic ringoptionally possessing one or more degrees of unsaturation, containingone or more heteroatomic substitutions selected from —S—, —SO—, —SO₂—,—O—, or —N—, optionally substituted with substitutents, including, butnot limited to, lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Such a ring optionally may be fused to oneor more of another “heterocyclic” ring(s). Examples of “heterocyclic”include, but are not limited to, pyrrole, furan, thiophene, imidazole,oxazole, thiazole, pyrazole, 3-pyrroline, pyrrolidine, pyridine,pyrimidine, purine, quinoline, isoquinoline, carbazole and the like.

The term C-linked heterocycle means a heterocycle that is bonded througha carbon atom, e.g. —(CH₂)_(n)-heterocycle where n is 1, 2 or 3 or—C<heterocycle where C<represents a carbon atom in a heterocycle ring.Similarly, R moieties that are N-linked heterocycles mean a heterocyclethat is bonded through a heterocycle ring nitrogen atom, e.g.—N<heterocycle where N<represents a nitrogen atom in a heterocycle ring.A variable group such as an R moiety that is bonded to a Formula Icompound can be a C-linked heterocycle or a N-linked heterocycle. Theseheterocycles include those listed below or described elsewhere herein.

Examples of heterocycles include by way of example and not limitationpyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidizedtetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl,pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl,indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl,piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl,6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl,pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl,2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl,indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,.beta.-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl,isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl,morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl,benzoxazolinyl, and isatinoyl.

By way of example and not limitation, carbon bonded heterocycles arebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Carbon bonded heterocycles include 2-pyridyl, 3-pyridyl,4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl,5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl,6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles arebonded at the nitrogen atom or position 1 of an aziridine, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of amorpholine, and position 9 of a carbazole, or beta.-carboline.Typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl,1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl and structuressuch as and tautomers of any of these.

“Heteroaryl” means an aromatic ring or two or more fused rings thatcontain one or more aromatic rings where the ring or fused ringscomprise 1, 2, 3 or more heteroatoms, usually oxygen (—O—), nitrogen(—NX—) or sulfur (—S—) where X is —H, a protecting group or optionallysubstituted alkyl. Examples are as described for heterocycle.

As used herein the term “isomer” refers to one of two or more moleculeshaving the same number and kind of atoms and hence the same molecularweight, but differing in respect to the arrangement or configuration ofthe atoms. Generally, differences in compounds having identicalmolecular and chemical formulas but differing in the way their atoms arearranged three-dimensionally in space create optically active isomers orenantiomers. These enantiomers are called (D- (for dexorotatory,right-handed or +) or L- (levorotatory, left-handed, or −) for thedirection in which they rotate plane-polarized light. A mixture of equalparts of the optical forms of a compound is known as a racemic mixtureor racemate. A racemic mixture is optically inactive, i.e., it consistsof equal parts of D- and L-enantiomers. The alpha-carbon atom of allamino acids (with the exception of glycine) is a center of asymmetry.This asymmetry likewise creates isomers having differences in thespatial orientation of their atoms in space. Although amino acids areoptically active such that the sign and magnitude of the opticalrotation of an amino acid is a function of the pH of the solution inwhich it is measured and of the nature of its side chain, the D or Ldesignation here does not refer to optical activity. Instead, itindicates absolute configurations relative to those of the relatedcompound glyceraldehyde.

The term “O-linked moiety” means a moiety that is bonded through anoxygen atom. Thus, when an R group is an O-linked moiety, that R isbonded through oxygen and it can thus be an ether, an ester (e.g.,—O—C(O)-optionally substituted alkyl), a carbonate or a carbamate (e.g.,—O—C(O)—NH₂ or —O—C(O)—NH-optionally substituted alkyl). Similarly, theterm “S-linked moiety” means a moiety that is bonded through a sulfuratom. Thus, when an R group is an S-linked moiety, that R is bondedthrough sulfur and it can thus be a thioether (e.g., —S-optionallysubstituted alkyl), a thioester (—S—C(O)-optionally substituted alkyl)or a disulfide (e.g., —S—S-optionally substituted alkyl). The term“N-linked moiety” means a moiety that is bonded through a nitrogen atom.Thus, when an R group is an N-linked moiety, the R group is bondedthrough nitrogen and one or more of these can thus be an N-linked aminoacid such as —NH—CH₂—COOH, a carbamate such as —NH—C(O)—O-optionallysubstituted alkyl, an amine such as —NH-optionally substituted alkyl, anamide such as —NH—C(O)-optionally substituted alkyl or —N₃. The term“C-linked moiety” means a moiety that is bonded through a carbon atom.When one or more R group is bonded through carbon, one or more of thesecan thus be—optionally substituted alkyl such as —CH₂—CH₂—O—CH₃,—C(O)-optionally substituted alkyl hydroxyalkyl, mercaptoalkyl,aminoalkyl or ═CH-optionally substituted alkyl.

As used herein, the term “ethoxy” refers to the substituent —O—CH₂CH₃.

As used herein, the term “methoxy” refers to the substituent —O—CH₃. Asused herein, the term “optionally” means that the subsequently describedevent(s) may or may not occur, and includes both event(s) which occurand events that do not occur.

As used herein the term “carbohydrate” refers to aldehyde or ketonecompounds with multiple hydroxyl groups. The term “monosaccharide” or“simple sugar” refers to a carbohydrate that does not hydrolyze.Examples of monosaccharides include glucose (dextrose), fructose,galactose, xylose and ribose. Monosaccharides are the building blocks ofdisaccharides like sucrose (common sugar) and polysaccharides (such ascellulose and starch). Further, each carbon atom that supports ahydroxyl group (except for the first and last) is chiral, giving rise toa number of isomeric forms all with the same chemical formula.

The term “configuration” as used herein refers to the three-dimensionalshape of a molecule. This shape is dependent on the preferred spatialorientation of covalent bonds to atoms having two or more bondingpartners. In order to represent three-dimensional configurations on atwo-dimensional surface, perspective drawings in which the direction ofa bond is specified by the line connecting the bonded atoms are used.Formula XIII shows an illustrative perspective drawing:

In formula XIII, the focus of configuration is a carbon (C) atom so thelines specifying bond directions will originate there. A simple straightline represents a bond lying approximately in the surface plane, asshown by the two bonds to substituent “A.” A wedge shaped bond isdirected in front of this plane (thick end toward the viewer), as shownby the bond to substituent “B.” A hatched bond is directed in back ofthe plane (away from the viewer), as shown by the bond to substituent“D.” A dashed bond represents a single or double bond which can be inthe cis or trans configuration.

The prostaglandin F_(2α) analog of the present invention is a compoundof Formula (I) or a salt of Formula (I):

wherein

R¹, R² and R³ each independently is H, C₁-C₆ alkyl, a phosphate group, amonosaccharide, a disaccharide or a polysaccharide;

the simple straight line represents a bond lying approximately in thesurface plane; the dashed bonds represent a single or double bond whichcan be in the cis or trans configuration, wherein there is at least onedouble bond; the wedge shaped bond is directed to the front of surfaceplane (thick end toward the viewer); and the hatched bond is directed inthe back of the surface plane (away from the viewer);

B is —O—, —S—, —SO—, —S(O₂)—, —(CH₂)_(a)—, where a is 0, 1, or 2, or—NR⁶—, where R⁶ is H or C₁-C₆ alkyl;

X is —NHR⁴, where R⁴ is OH, alkyl, alkenyl, aryl, cycloalkyl,alkylcycloalkyl, cycloalkenyl, a heterocycle, or a carbamate; X is acyclic substituent in which nitrogen is part of the ring, represented as—N(R⁴)₂, wherein (R⁴)₂ is —(CH₂)_(k)— where k is 2 to 10; or X is —OR⁵,where R⁵ is H, alkyl, alkenyl, aryl, cycloalkyl, alkylcycloalkyl, aheterocycle or a carbamate;

W_(m), wherein m is 0 or greater, is such that any of the carbons on thearyl ring may be replaced by at least two heteroatoms selected from thegroup consisting of N, S and O;

n is a whole number between 0 and 5; and

Y is one or more C₁-C₅ alkyl groups, C₁-C₅ haloalkyl groups, C₁-C₅alkoxy groups, C₁-C₅ haloalkoxy groups, C₁-C₅ aliphatic acylaminogroups, nitro groups, halogen atoms, an aromatic heterocyclic grouphaving 5-6 ring atoms and having at least one heteroatom, the heteroatombeing N, O, or S; a C₃-C₇ cycloalkane or a C₃-C₇ cycloalkene optionallysubstituted with C₁-C₅ alkyl groups.

In preferred embodiments,

X is

NHR⁴, wherein R⁴ is OH, alkenyl, aryl, cycloalkyl, alkylcycloalkyl,cycloalkenyl, a heterocycle, or a carbamate;

a cyclic substituent in which nitrogen is part of the ring, representedas —N(R⁴)₂, wherein (R⁴)₂ is —(CH₂)_(k)— where k is 2 to 10; or

OR⁵, where R⁵ is alkenyl, aryl, alkylcycloalkyl, a heterocycle or acarbamate; and

R¹, R² and R³ each independently is H, C₁-C₆ alkyl, a phosphate group, amonosaccharide, a disaccharide or a polysaccharide;

the simple straight line represents a bond lying approximately in thesurface plane; the dashed bonds represent a single or double bond whichcan be in the cis or trans configuration, wherein there is at least onedouble bond; the wedge shaped bond is directed to the front of surfaceplane; and the hatched bond is directed in the back of the surfaceplane;

B is —O—, —S—, —(CH₂)_(a)—, where a is 0, 1, or 2, or —NR⁶—, where R⁶ isH or C₁-C₆ alkyl; —SO— or (SO)₂, such that optically active isomers areincluded whenever chiral centers are present;

W_(m) wherein m is 0 or greater, is such that any of the carbons on thearyl ring may be replaced by at least two heteroatoms selected from thegroup consisting of N, S and O;

n is a whole number between 0 and 5; and

Y is one or more C₁-C₅ alkyl groups, C₁-C₅ haloalkyl groups, C₁-C₅alkoxy groups, C₁-C₅ haloalkoxy groups, C₁-C₅ aliphatic acylaminogroups, nitro groups, halogen atoms, an aromatic heterocyclic grouphaving 5-6 ring atoms and having at least one heteroatom, the heteroatombeing N, O, or S; a C₃-C₇ cycloalkane or a C₃-C₇ cycloalkene optionallysubstituted with C₁-C₅ alkyl groups.

In some embodiments, when X is NHR⁴, wherein R⁴ is OH, alkenyl, aryl,cycloalkyl, alkylcycloalkyl, cycloalkenyl, a heterocycle, or acarbamate, R¹, R² and R³ each independently is H, B is —(CH₂)_(a)—,where a is 0, 1, or 2, and m and n are 0. In some embodiments, when X isNHR⁴ and R⁴ is OH, alkenyl, aryl, cycloalkyl, alkylcycloalkyl,cycloalkenyl, a heterocycle, or a carbamate, R¹, R² and R³ eachindependently is H, B is —O—, and m and n are 0. In some embodiments,when X is NHR⁴ and R⁴ is OH, alkenyl, aryl, cycloalkyl, alkylcycloalkyl,cycloalkenyl, a heterocycle, or a carbamate, R¹, R² and R³ eachindependently is H, B is —S—, and m and n are 0. In some embodiments,when X is NHR⁴ and R⁴ is OH, alkenyl, aryl, cycloalkyl, alkylcycloalkyl,cycloalkenyl, a heterocycle, or a carbamate, R¹, R² and R³ eachindependently is H, B is —SO—, and m and n are 0. In some embodiments,when X is NHR⁴ and R⁴ is OH, alkenyl, aryl, cycloalkyl, alkylcycloalkyl,cycloalkenyl, a heterocycle, or a carbamate, R¹, R² and R³ eachindependently is H, B is —S(O)₂—, and m and n are 0. In someembodiments, when X is NHR⁴ and R⁴ is OH, alkenyl, aryl, cycloalkyl,alkylcycloalkyl, cycloalkenyl, a heterocycle, or a carbamate, R¹, R² andR³ each independently is H, B is —NR⁶— where R⁶ is H or C₁-C₆ alkyl andm and n are 0.

In some embodiments, when X is a cyclic substituent in which nitrogen ispart of the ring, represented as —N(R⁴)₂ and (R⁴)₂ is —(CH₂)_(k) where kis 2 to 10, R¹, R² and R³ each independently is H, B is —(CH₂)_(a)—,where a is 0, 1, or 2, and m and n are 0. In some embodiments, when X is—N(R⁴)₂ and (R⁴)₂ is —(CH₂)_(k) where k is 2 to 10, R¹, R² and R³ eachindependently is H, B is —O—, and m and n are 0. In some embodiments,when X is —N(R⁴)₂ and (R⁴)₂ is —(CH₂)_(k)— where k is 2 to 10, R¹, R²and R³ each independently is H, B is —S—, and m and n are 0. In someembodiments, when X is —N(R⁴)₂ and (R⁴)₂ is —(CH₂)_(k) where k is 2 to10, R¹, R² and R³ each independently is H, B is —SO—, and m and n are 0.In some embodiments, when X is —N(R⁴)₂ and (R⁴)₂ is —(CH₂)_(k)— where kis 2 to 10, R¹, R² and R³ each independently is H, B is —SO₂—, and m andn are 0. In some embodiments, when X is —N(R⁴)₂ and (R⁴)₂ is —(CH₂)_(k)where k is 2 to 10, R¹, R² and R³ each independently is H, B is —NR⁶—where R⁶ is H or C₁-C₆ alkyl and m and n are 0.

In some embodiments, when X is OR⁵, R⁵ is alkenyl, aryl,alkylcycloalkyl, a heterocycle or a carbamate. In some such embodiments,R¹, R² and R³ each independently is H, B is —(CH₂)_(a)—, where a is 0,1, or 2, and m and n are 0. In some such embodiments, R¹, R² and R³ eachindependently is H, B is —O—, and m and n are 0. In some suchembodiments, R¹, R² and R³ each independently is H, B is —S—, and m andn are 0. In some such embodiments, R¹, R² and R³ each independently isH, B is —SO—, and m and n are 0. In some such embodiments, R¹, R² and R³each independently is H, B is —SO₂—, and m and n are 0. In someembodiments, B is —NR⁶— where R⁶ is H or C₁-C₆ alkyl and m and n are 0.

In one embodiment, R¹, R², and R³ are H, X is a nitrogen-linkedcyclopropyl group, B is —CH₂—, a is 1, and both m and n are 0. Thiscompound of Formula I is 17 phenyl trinor PGF_(2α) cyclopropylamide,which has the structure:

wherein the simple straight line represents a bond lying approximatelyin the surface plane; the wedge shaped bond is directed to the front ofsurface plane; and the hatched bond is directed in the back of thesurface plane.

In another embodiment, R¹, R², and R³ are H, X is a nitrogen-linkedmethyl cyclopropyl group, B is —CH₂—, a is 1, and both m and n are 0.This compound is 17 phenyl trinor PGF_(2α) cyclopropyl methyl amide,which has the structure:

wherein the simple straight line represents a bond lying approximatelyin the surface plane; the wedge shaped bond is directed to the front ofsurface plane; and the hatched bond is directed in the back of thesurface plane.

In yet another embodiment, R¹ is a phosphate group, R² is H, R³ is H, Bis O, m and n are 0 and X is an oxygen-linked cyclopropyl group. Thiscompound of Formula I has the structure:

wherein the simple straight line represents a bond lying approximatelyin the surface plane; the dashed bonds represent a single or double bondwhich can be in the cis or trans configuration, wherein there is atleast one double bond; the wedge shaped bond is directed to the front ofsurface plane; and the hatched bond is directed in the back of thesurface plane.

In another embodiment, R¹, R², and R³ are each H, X is a nitrogen-linkedcyclopropyl group, B is —O— and m and n are 0. This compound of FormulaI has the structure:

wherein the simple straight line represents a bond lying approximatelyin the surface plane; the wedge shaped bond is directed to the front ofsurface plane; and the hatched bond is directed in the back of thesurface plane. This compound is 16-phenoxy tetranor PGF_(2α) cyclopropylamide.

In another embodiment, R¹, R², and R³ are each H, X is a nitrogen-linkedmethyl cyclopropyl group, B is —O— and m and n are 0. This compound is16-phenoxy tetranor PGF_(2α) cyclopropyl methyl amide, which has thestructure:

wherein the simple straight line represents a bond lying approximatelyin the surface plane; the wedge shaped bond is directed to the front ofsurface plane; and the hatched bond is directed in the back of thesurface plane.

In another embodiment, R¹, R², and R³ are each H, X is a nitrogen-linkedcyclopropyl group, B is CH₂ where a is 1, and n is 0 and m is 2. Thiscompound of Formula I has the structure:

wherein the simple straight line represents a bond lying approximatelyin the surface plane; the dashed bonds represent a single or double bondwhich can be in the cis or trans configuration, wherein there is atleast one double bond; the wedge shaped bond is directed to the front ofsurface plane; and the hatched bond is directed in the back of thesurface plane.

In another embodiment, R¹ is a phosphate group, R² is H, R³ is H, B isSO, m and n are 0 and X is an oxygen-linked cyclopropyl group. Thiscompound of Formula I has the structure:

wherein the simple straight line represents a bond lying approximatelyin the surface plane; the dashed bonds represent a single or double bondwhich can be in the cis or trans configuration, wherein there is atleast one double bond; the wedge shaped bond is directed to the front ofsurface plane; and the hatched bond is directed in the back of thesurface plane.

In yet another embodiment, R¹ is a monosaccharide (e.g., glucose), R²and R³ are H, X is a nitrogen-linked ethyl group; B is —CH₂ where a is1, and m and n are 0. This compound of Formula I has the structure:

wherein the simple straight line represents a bond lying approximatelyin the surface plane; the dashed bonds represent a single or double bondwhich can be in the cis or trans configuration, wherein there is atleast one double bond; the wedge shaped bond is directed to the front ofsurface plane; and the hatched bond is directed in the back of thesurface plane.

In yet another embodiment, R¹ is a monosaccharide (e.g., glucose), R²and R³ are H, X is a nitrogen-linked ethyl group; B is —CH₂ where a is1, n is 2, and Y is a cyclopropyl group linked to a nitrogen heteroatom.This compound of Formula I has the structure:

wherein the simple straight line represents a bond lying approximatelyin the surface plane; the dashed bonds represent a single or double bondwhich can be in the cis or trans configuration, wherein there is atleast one double bond; the wedge shaped bond is directed to the front ofsurface plane; and the hatched bond is directed in the back of thesurface plane.

In another embodiment, R¹, R² and R³ each are —OH; X is NHR⁴, where R⁴is cyclopropyl; B is —O; m=0; Y is Cl; and n=1. This compound of FormulaI has the structure:

wherein the simple straight line represents a bond lying approximatelyin the surface plane; the wedge shaped bond is directed to the front ofsurface plane; and the hatched bond is directed in the back of thesurface plane. This compound is (16-(3-chlorophenoxy)-17, 18, 19,20-tetranor PGF_(2α)) cyclopropyl amide.

In another embodiment, R¹, R² and R³ each are —OH; X is NHR⁴, where R⁴is cyclopropyl methyl amide; B is —O; m=0; Y is Cl; and n=1. Thiscompound of Formula I has the structure:

wherein the simple straight line represents a bond lying approximatelyin the surface plane; the wedge shaped bond is directed to the front ofsurface plane; and the hatched bond is directed in the back of thesurface plane. This compound is (16-(3-chlorophenoxy)-17, 18, 19,20-tetranor PGF_(2α)) cyclopropyl methyl amide. The compounds of thepresent invention can be formulated into pharmaceutical compositions. Asused herein, “pharmaceutically acceptable salts” include, but are notlimited to, those formed with free amino groups such as those derivedfrom hydrochloric, phosphoric, sulfuric, acetic, oxalic, tartaric acids,etc., and those formed with free carboxyl groups, including, but notlimited to, those derived from sodium, potassium, ammonium, calcium,ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol,histidine, procaine, and the like.

The compounds of the present invention may be used in methods to treatan epithelial-related condition, the method comprising the steps (a)preparing at least one compound of the present invention; (b)formulating a composition with the at least one compound; and (c)administering the composition to a subject in need thereof.

The present invention provides topical compositions for treating anepithelial-related condition comprising hair loss in a subject in needof treatment thereof, including a human, that includes a compound of theinvention and a carrier.

The phrase “epithelia” or “epithelial” or “epithelial tissues” as usedherein is meant to include skin and mucosal membranes. Thus, the presentinvention offers compositions useful for treating a condition of theskin or a mucosal membrane, such as, but not limited to, that of a nose,an eye, a face, lip, and a scalp.

The term “topical” refers to administration of an inventive compositionat, or immediately beneath, the point of application.

The phrase “topically applying” describes application onto one or moresurfaces(s) including epithelial surfaces. “Topically applying” refersto direct application to the area of the surface to be affected. Thecomposition may be applied by pouring, dropping, or spraying, if aliquid; rubbing on, if an ointment, lotion, cream, gel, or the like;dusting, if a powder; spraying, if a liquid or aerosol composition; orby any other appropriate means.

In another embodiment, the present invention provides a topicalpharmaceutical composition for treating an epithelial-related conditioncomprising hair loss in a subject, including a human, in need oftreatment thereof that includes at least one compound of the inventionand a carrier.

In a further embodiment, the present invention provides a topicalcosmetic composition for treating an epithelial-related conditioncomprising hair loss in a subject, including a human, in need oftreatment thereof that includes at least one compound of the inventionand a carrier.

In another embodiment, provided herein is a method of treating anepithelial-related condition comprising hair loss, the method includingthe step of topically applying onto an epithelial surface of a mammal,including a human, in need thereof a pharmaceutically effective amountof a composition that includes at least one compound of the inventionand a carrier.

In a further embodiment, the invention provides a method of treating anepithelial-related condition comprising hair loss, the method includingthe step of topically applying onto a surface of a subject, including ahuman, in need thereof a cosmetically effective amount of a compositionthat includes at least one compound of the present invention and acarrier.

In a further embodiment, the invention provides a method of preparing atopical composition, the method including the step of admixing at leastone compound of the present invention and a carrier.

The inventors have recognized that inventive compositions containing thecompounds of the invention can be used effectively in topicalapplications to treat cosmetic conditions. These inventive compositionsdo not exhibit systemic effects when topically applied.

The compositions of the present invention may be usefully employed incosmetic, cosmeceutical and general skincare compositions as well as inpharmaceutical compositions.

In one embodiment, the composition of the invention is a pharmaceuticalcomposition. As used herein, a “pharmaceutical composition” refers to acomposition that is employed to prevent, reduce in intensity, cure orotherwise treat a target condition.

In another embodiment, the composition of the invention is a cosmeticcomposition. As used herein a “cosmetic composition” refers to acomposition that is intended to be rubbed, poured, sprinkled, or sprayedon, introduced into, or otherwise applied to a subject or any partthereof for cleansing, beautifying, promoting attractiveness, oraltering the appearance, or an article intended for use as a componentof any such article, except that such term does not include soap.

In another embodiment, the composition of the invention is acosmeceutical composition. As used herein the term “cosmeceuticalcomposition” refers to a composition that is employed as both a cosmeticcomposition and as a pharmaceutical composition.

In another embodiment, the composition of the invention is a cosmeticcomposition that restores hair pigmentation to depigmented hair.

Hair color is the result of pigmentation of the hair. Stem cells at thebase of hair follicles are responsible for producing melanocytes, thecells that produce and store pigment in hair and skin. At some point inthe aging process, these cells make less and less pigment, until thehair has very little pigment. White hair has no pigment, while gray hairhas some pigment.

The graying process usually is gradual. However, it has been noted thattobacco smoking may cause premature graying. Additionally, there are anumber of medical conditions that affect hair color. For example,albinism is a genetic abnormality in which no pigment is found in humanhair, eyes or skin. Vitiligo is the patchy loss of hair and skin colorthat may occur as the result of an autoimmune disease. Malnutrition,which is reversible with proper nutrition, is known to cause hair tobecome lighter, thinner, and more brittle. Patients suffering fromWerner syndrome, a rare autosomal recessive disorder that resemblesaccelerated aging, develop many of the changes associated with aging asyoung adults, including the graying and loss of hair. Pernicious anemiadue to B₁₂ deficiency also can cause premature graying.

In another aspect of the present invention, the composition of thepresent invention includes a carrier. As used herein “carrier” describesa material that does not cause significant irritation to an organism anddoes not abrogate the biological activity and properties of the compoundof the composition of the present invention. Carriers must be ofsufficiently high purity and of sufficiently low toxicity to render themsuitable for administration to the mammal being treated. The carrier canbe inert, or it can possess pharmaceutical benefits, cosmetic benefitsor both.

Some non-limiting representative examples of carriers includemoisturizing agents or humectants, pH adjusting agents, hairconditioning agents, chelating agents, preservatives, emulsifiers,thickeners, solubilizing agents, penetration enhancers, anti-irritants,colorants and surfactants.

As used herein a “moisturizing agent” is a substance that adds orrestores moisture to the skin. Representative examples of moisturizingor humectant agents that are usable in the present invention include,without limitation, guanidine, glycolic acid and glycolate salts (e.g.ammonium salt and quaternary alkyl ammonium salt), aloe vera in any ofits variety of forms (e.g., aloe vera gel), allantoin, urazole,polyhydroxy alcohols such as sorbitol, glycerol, hexanetriol, propyleneglycol, butylene glycol, hexylene glycol and the like, polyethyleneglycols, sugars and starches, sugar and starch derivatives (e.g.,alkoxylated glucose), hyaluronic acid, lactamide monoethanolamine,acetamide monoethanolamine and any combination thereof.

As is widely recognized in the art, since the pH of the skin is 5.5,compositions for topical skin application (to avoid irritation) can havea pH value of between about pH 4.0 and about pH 7.0, or between about pH5.0 and about pH 6.0, or about pH 5.5 or substantially pH 5.5. Hence, apH adjusting composition is typically added to bring the pH of thecomposition to the desired value. The compositions of the presentinvention therefore may be formulated to have a pH value of about 7.2.Suitable pH adjusting agents include, for example, but are not limitedto, one or more adipic acids, glycines, citric acids, calciumhydroxides, magnesium aluminometasilicates, buffers or any combinationsthereof.

Suitable hair conditioning agents that can be used in the context of thepresent invention include, for example, one or more collagens, cationicsurfactants, modified silicones, proteins, keratins, dimethiconepolyols, quaternary ammonium compounds, halogenated quaternary ammoniumcompounds, alkoxylated carboxylic acids, alkoxylated alcohols,alkoxylated amides, sorbitan derivatives, esters, polymeric ethers,glyceryl esters, or any combinations thereof.

Hair stimulating agents may be added to the compositions of the presentinvention. For example Procapil® (FR 2 791 684 and WO0058347) promotesthe visible appearance of thicker and fuller hair and prevents prematurehair thinning and hair loss by boosting the synthesis of components atthe epidermal junction where the hair anchors to the skin, which helpsto anchor the hair follicles more firmly to the scalp. U.S. Pat. No.6,861,077 describes methods to protect keratinous fibers from extrinsicdamages comprising application of compositions comprising at least oneplant extract. For example, a plant extract composed of purifiedglycoproteins obtained from white potatoes (Solanum tuberosum L. iscommercially available from SEDERMA, Inc. (France) as Dermolectine® andCapilectine®. ANCRIN® (Sederma), a hydroglycolic solution containingoctylbutyrate and glutamine peptide, reduces hair loss by supplying avegetable substrate to transglutaminases, a group of enzymes known toincrease protein reticulation in the scalp and help anchor the hair tothe scalp. Capisome™ (Sederma) is a liposome that comprises homotaurine(3-aminopropane sulfonic acid), a bacterial filtrate of biotechnologicalorigin from enterobacteria that contains high levels of peptides and thesulfur-containing amino acids methionine and cysteine; and marinesulfopolysaccharides. (See U.S. Pat. No. 6,376,557, incorporated hereinby reference). Capigen™ (Sederma), is a complex that compriseshomotaurine (3-aminopropane sulfonic acid), a bacterial filtrateobtained from a strain of microorganisms cultured in a medium comprisingselected peptides, with the filtrate containing high levels of peptides,and a sulfomuycopolysaccharide of marine origin, which is a complex ofsulfated polysaccharides that are soluble in water and are found in theconnective tissue and synovial fluids. Follicusan® (ChemlishesLaboratorium Dr. Kurt Richter GmbH), is composed of a fraction derivedfrom milk, ethyl pantenol, inositol and sulfur-containing amino acids(N-acetylcysteine and N-acetyl methionine in an aqueous alcoholicmedium. Anageline® (Silab) contains an extract from white sweet lupine.Cprillisil (Exsymol S.A.M. of Monaco) is a 20% solution ofdimethylsilanediol salicilate in butylenes glycol with triethanolamine.Mahanimba is an extract of the flowers and inflorescence of the neemtree (Melia azadirachta) and contains carotinoids, amino acids,phytosterols, mucins, polyacetylenes, and ses quiterpenes. Malkagni isan extract of the seeds, leaves and flowers of the intellect tree(Celastrus paniculata) and contains tannins, mineral salts, saponins,and iridic glycosides. Fitopur B is a complex available from Sederma,Inc., and comprises extracts of three plants: buchu (Buc hu barosma),henna (Lawsonia inermis), and venus hair (Adiatium capillus-veneris).The essential oil of buchu contains the terpenic oil diosphenol andsulfur compounds. The leaves of henna contain flavonic pigments,including luteoline and laxanthones, principally lawsone. Venus hair isa small fir native to the south of France; it has diuretic and emollientactivity. Peptide-copper complexes containing dipeptides or tripeptideschelated to copper stimulate hair growth (see U.S. Pat. No. 5,538,945and U.S. Pat. No. 6,017,888, incorporated herein by reference). Hormonereplacement therapy (HRT), including administration of micronizedprogesterone pills and creams and estrogen pills and creams, is used totreat androgenetic alopecia for women. Other such agents are known bypersons of skill in the art.

Chelating agents are optionally added to the compositions of the presentinvention so as to enhance the preservative or preservative system.Chelating agents that are mild agents, such as, for example,ethylenediaminetetraacetic acid (EDTA), EDTA derivatives, or anycombination thereof, are particularly useful.

Suitable preservatives for use in the compositions of the presentcomposition include, without limitation, one or more alkanols, disodiumEDTA (ethylenediamine tetraacetate), EDTA salts, EDTA fatty acidconjugates, isothiazolinone, parabens such as methylparaben andpropylparaben, propylene glycols, sorbates, urea derivatives such asdiazolindinyl urea, or any combinations thereof.

“Emulsifiers” as used herein promote the formation and stabilization ofan emulsion. Suitable emulsifiers may be natural materials, finelydivided solids, or synthetic materials. Natural emulsifying agents maybe derived from either animal or vegetable sources. Those from animalsources include gelatin, egg yolk, casein, wool fat, or cholesterol.Those from vegetable sources include acacia, tragacanth, chondrus, orpectin. Vegetable sources specifically from cellulose derivativesinclude methyl cellulose and carboxymethyl cellulose to increase theviscosity. Finely divided emulsifiers include bentonite, magnesiumhydroxide, aluminum hydroxide, or magnesium trisilicate. Syntheticagents include anionic, cationic or nonionic agents. Particularly usefulare sodium lauryl sulfate, benzalkonium chloride or polyethylene glycol400 monostearate, or any combinations thereof.

“Thickeners” as used herein refer to agents that make the composition ofthe present invention dense or viscous in consistency. Suitablethickeners that can be used in the context of the present inventioninclude, for example, non-ionic water-soluble polymers such ashydroxyethylcellulose (commercially available under the TrademarkNatrosol® 250 or 350), cationic water-soluble polymers such as Polyquat37 (commercially available under the Trademark Synthalen® CN), fattyalcohols, fatty acids, anionic polymers, and their alkali salts andmixtures thereof.

As used herein, the term “solubilizing agents” refers to thosesubstances that enable solutes to dissolve. Representative examples ofsolubilizing agents that are usable in the context of the presentinvention include, without limitation, complex-forming solubilizers suchas citric acid, ethylenediamine-tetraacetate, sodium meta-phosphate,succinic acid, urea, cyclodextrin, polyvinylpyrrolidone,diethylammonium-ortho-benzoate, and micelle-forming solubilizers such asTWEEN® and spans, e.g., TWEEN 80®. Other solubilizers that are usablefor the compositions of the present invention are, for example,polyoxyethylene sorbitan fatty acid ester, polyoxyethylene n-alkylethers, n-alkyl amine n-oxides, polyoxamers, organic solvents, such asacetone, phospholipids and cyclodextrins.

The term “penetration enhancer” as used herein refers to an agent knownto accelerate the delivery of a substance through the skin. Suitablepenetration enhancers usable in the present invention include, but arenot limited to, a vegetable oil. Such oils include, for example,safflower oil, cottonseed oil and corn oil.

Additional thickeners, penetration enhancers and other adjuvants maygenerally be found in Remington's Pharmaceutical Sciences, 18th or 19theditions, published by the Mack Publishing Company of Easton, Pa. whichis incorporated herein by reference.

As used herein, an “anti-irritant” refers to an agent that prevents orreduces soreness, roughness, or inflammation of a bodily part. Suitableanti-irritants that can be used in the context of the present inventioninclude, for example, steroidal and non steroidal anti-inflammatoryagents or other materials such as aloe vera, chamomile, alpha-bisabolol,cola nitida extract, green tea extract, tea tree oil, licorice extract,allantoin, caffeine or other xanthines, glycyrrhizic acid and itsderivatives.

The presently known anti-irritants can be divided into water-solubleanti-irritants and water-insoluble anti-irritants. Representativeexamples of such compositions are described, for example, in U.S. Pat.No. 5,482,710 which is herein incorporated by reference.

Colorants may also be used in the compositions of the invention.Colorants include pigments or dyes or a combination thereof as thecosmetic benefit requires. Preferred pigments include, but are notlimited to, iron oxides, and titanium oxides. Suitable dyes include FD&Capproved colorants, D&C approved colorants, and those approved for usein Europe and Japan (see Marmion, D. M., Handbook of US Colorants forFood, Drugs, Cosmetics, and Medical Devices, 3rd ed, 1991 hereinincorporated by reference). The term “color” as used herein refers tothe quality of an object or substance with respect to light reflected orabsorbed by the object or substance. The three characteristics of colorare hue, intensity, and value. “Hue” refers to a gradation, tint, orvariety of a color. “Intensity”, “chroma”, and “saturation” are usedinterchangeably to refer to the strength or sharpness of a color. Acolor is full in intensity only when pure and unmixed. “Value” refers toa degree of lightness or darkness in a color.

The term “surfactants” as used herein refers to surface-activesubstances, such as a detergent. Suitable surfactants for use with theinventive compositions include, but are not limited to, sarcosinates,glutamates, sodium alkyl sulfates, ammonium alkyl sulfates, sodiumalkyleth sulfates, ammonium alkyleth sulfates, ammoniumlaureth-n-sulfates, sodium laureth-n-sulfates, isothionates,glycerylether sulfonates, sulfosuccinates and combinations thereof. Morepreferably, the anionic surfactant is selected from the group consistingof sodium lauroyl sarcosinate, monosodium lauroyl glutamate, sodiumalkyl sulfates, ammonium alkyl sulfates, sodium alkyleth sulfates,ammonium alkyleth sulfates, and combinations thereof.

In some embodiments, a pharmaceutically acceptable carrier is includedin the composition. As used herein the term “pharmaceutically acceptablecarrier” refers to any substantially non-toxic carrier conventionallyuseable for topical administration of pharmaceuticals in which thecompound will remain stable and bioavailable when applied directly toskin or mucosal surfaces.

In another embodiment, the compositions of the present invention includea cosmetically acceptable carrier. As used herein the phrase“cosmetically acceptable carrier” refers to a substantially non-toxiccarrier, conventionally useable for the topical administration ofcosmetics, with which compounds will remain stable and bioavailable. Itwill be understood that cosmetically acceptable carriers andpharmaceutically acceptable carriers are similar, if not oftenidentical, in nature.

Suitable pharmaceutically acceptable carriers include water, petroleumjelly (Vaseline™), petroleum, mineral oil, vegetable oil, animal oil,organic and inorganic waxes, such as microcrystalline, paraffin andozocerite wax, natural polymers, such as xanthanes, gelatin, cellulose,collagen, starch, or gum arabic, alcohols, polyols, and the like. Alsoincluded are the carriers described hereinabove.

In another embodiment, the pharmaceutically acceptable carrier of thecomposition of the present invention includes a sustained release ordelayed release carrier. The carrier can be any material capable ofsustained or delayed release of the compound to provide a more efficientadministration resulting in less frequent and/or decreased dosage of thecompound, ease of handling, and extended or delayed effects onepithelial-related conditions. Non-limiting examples of such carriersinclude liposomes, microsponges, microspheres, or microcapsules ofnatural and synthetic polymers and the like. Liposomes which may enhancethe localized delivery of the compounds of the inventive compositionwithin skin layers, may be formed from a variety of phospholipids, suchas cholesterol, stearylamines or phosphatidylcholines.

Suitable cosmetically acceptable carriers are described in the CTFAInternational Cosmetic Ingredient Dictionary and Handbook, 8th edition,edited by Wenninger and Canterbery, (The Cosmetic, Toiletry, andFragrance Association, Inc., Washington, D.C., 2000), which is hereinincorporated by reference. Also included are the carriers describedhereinabove.

In another embodiment, the compositions of the present invention canfurther include one or more additional compatible active ingredients,which are aimed at providing the composition with anotherpharmaceutical, cosmeceutical or cosmetic effect, in addition to thatprovided by a compound of the inventive composition. “Compatible” asused herein means that the components of such a composition are capableof being combined with each other in a manner such that there is nointeraction that would substantially reduce the efficacy of thecomposition under ordinary use conditions.

In one embodiment, the compound of the inventive compositions is anactive ingredient.

As used herein, the phrase “additional active ingredient” refers to anagent, other than a compound of the inventive composition, that exerts apharmacological, dermatological or any other beneficial activity. It isto be understood that “other beneficial activity” may be one that isonly perceived as such by the subject using the inventive compositions.

In another embodiment, the compound of the inventive composition is anew excipient. As used herein a “new excipient” means any inactiveingredient that is intentionally added to the composition of the presentinvention and is not intended to exert therapeutic effects at theintended dosage, although it may act to improve product delivery. A newexcipient is not fully qualified by existing safety data with respect tothe currently proposed level of exposure, duration of exposure or routeof administration. Additional characteristics of new excipients can befound in the Guidance for Industry Nonclinical Studies for the SafetyEvaluation of Pharmaceutical Excipients issued by the US Food and DrugAdministration Center for Drug Evaluation and Research, in May, 2005,herein incorporated by reference.

Compositions according to the present invention, which further includeone or more additional active ingredients, can therefore be furtherefficiently used, in addition to their use as a treatment for anepithelial-related condition, in the treatment of any medical, cosmeticand/or cosmeceutical condition in which applying the additional activeingredient is beneficial.

Additional active ingredients included in the compositions according tothe present invention used to treat an epithelial-related conditioninclude, without limitation, one or more, in any combination, of aprotective agent, an emollient, an astringent, an irritant, akeratolytic, a sun screening agent, a sun tanning agent, an antibioticagent, an antifungal agent, an antiviral agent, an antiprotozoal agent,an anti-acne agent, an anesthetic agent, a steroidal anti-inflammatoryagent, a non-steroidal anti-inflammatory agent, an antipruritic agent,an anti-oxidant agent, a chemotherapeutic agent, an anti-histamineagent, a vitamin, a hormone, an anti-dandruff agent, an anti-wrinkleagent, an anti-skin atrophy agent, a sclerosing agent, a cleansingagent, a caustic agent and a hypo-pigmenting agent.

In the broadest pharmacological sense, a “protective” is any agent thatisolates the exposed surface of the skin or other membrane from harmfulor annoying stimuli. Protectives as described herein may take the formof dusting powders, adsorbents, mechanical protective agents, andplasters. Dusting powders are relatively inert and insoluble materialsthat are used to cover and protect epithelial surfaces, ulcers andwounds. Usually, these substances are finely subdivided powders thatabsorb moisture and can act as a desiccant. The absorption of skinmoisture decreases friction and also discourages certain bacterialgrowth. Some of the materials used as protective adsorbents includebentonite, insoluble salts of bismuth, boric acid, calcium carbonate,(precipitated), cellulose, corn starch, magnesium stearate, talc,titanium dioxide, zinc oxide, and zinc stearate.

Protectives also can be administered to the skin to form an adherent,continuous film that may be flexible or semi-rigid depending on thematerials and the formulations as well as the manner in which they areapplied. This material may serve several purposes including providingocclusion from the external environment, providing chemical support, andserving as vehicles for other medicaments. Mechanical protectives aregenerally either collodions or plasters. Examples include aluminumhydroxide gel, collodium, dimethicone, petrolatum gauze, absorbablegelatin film, absorbable gelatin sponge, zinc gelatin, kaolin, lanolin,anhydrous lanolin, mineral oil, mineral oil emulsion, mineral oil light,olive oil, peanut oil, petrolatum, silicones, hydrocolloids and thelike.

In some embodiments, protectives included in the composition of theinvention are demulcents. Demulcents are protective agents employedprimarily to alleviate irritation, particularly mucous membranes orabraded tissues. They often are applied to the surface in a viscid,sticky preparation that covers the area readily and may be medicated. Anumber of chemical substances possess demulcent properties. Thesesubstances include the alginates, mucilages, gums, dextrins, starches,certain sugars, and polymeric polyhydric glycols. Others include acacia,agar, benzoin, carbomer, gelatin, glycerin, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, propyleneglycol, sodium alginate, tragacanth, hydrogels and the like.

“Emollients” are generally bland, fatty or oleaginous materials whichcan be applied locally, particularly to the skin. Emollients increasethe tissue moisture content, thereby rendering the skin softer and morepliable. Increased moisture content in the skin can be achieved bypreventing water loss with an occlusive water-immiscible barrier, byincreasing the water-holding capacity in the skin with humectants, or byaltering the desquamation of the outermost skin layer, the stratumcorneum. Useful emollients include lanolin, spermaceti, mineral oil,paraffin, petrolatum, white ointment, white petroleum, yellow ointment.Also included are vegetable oils, waxes, cetyl alcohol, glycerin,hydrophilic petrolatum, isopropyl myristate, myristyl alcohol, and oleylalcohol.

“Astringents” are locally applied, generally protein precipitants, thathave such a low cell penetrability that the action essentially islimited to the cell surface and interstitial spaces. The astringentaction is accompanied by contraction and wrinkling of the tissue and byblanching. Astringents are used therapeutically to arrest hemorrhage bycoagulating the blood, to promote healing, to toughen the skin or todecrease sweating. The principal components of astringents are salts ofaluminum, zinc, manganese, iron or bismuth.

An “irritant” is a material that acts locally on the skin to induce,based on irritant concentration, hyperemia (meaning an excess of bloodin an area or body part, usually indicated by red, flushed color or heatin the area), inflammation, and desiccation. Irritant agents include,but are not limited to, alcohol, aromatic ammonia spirits, benzointincture, camphor capsicum, and coal tar extracts. In some embodiments,the irritant is a rubefacient. As used herein “rubefacients” are agentsthat induce hyperemia, wherein hyperemia means an increased amount ofblood in a body part or organ. Rubefaction, which is induced byrubefacients, results from increased circulation to an injured area andis accompanied by a feeling of comfort, warmth, itching andhyperesthesia.

“Keratolytics” (desquamating agents) act to remove outer layers of thestratum corneum. This is particularly useful in hyperkeratotic areas.The keratolytics include benzoyl peroxide, fluorouracil, resorcinol,salicylic acid, tretinoin, and the like.

Representative examples of sun screening agents usable in context of thepresent invention include, without limitation, p-aminobenzoic acid andits salts and derivatives thereof (ethyl, isobutyl, glyceryl esters;p-dimethylaminobenzoic acid); anthranilates (i.e., o-amino-benzoates;methyl, menthyl, phenyl, benzyl, phenylethyl, linalyl, terpinyl, andcyclohexenyl esters); salicylates (amyl, phenyl, octyl, benzyl, menthyl,glyceryl, and di-propylene glycol esters); cinnamic acid derivatives(menthyl and benzyl esters, a-phenyl cinnamonitrile; butyl cinnamoylpyruvate); dihydroxycinnamic acid derivatives (umbelliferone,methylumbelliferone, methylaceto-umbelliferone); trihydroxy-cinnamicacid derivatives (esculetin, methylesculetin, daphnetin, and theglucosides, esculin and daphnin); hydrocarbons (diphenylbutadiene,stilbene); dibenzylacetone and benzylacetophenone; naphtholsulfonates(sodium salts of 2-naphthol-3,6-disulfonic and of2-naphthol-6,8-disulfonic acids); di-hydroxynaphthoic acid and itssalts; o- and p-hydroxybiphenyldisulfonates; coumarin derivatives(7-hydroxy, 7-methyl, 3-phenyl); diazoles (2-acetyl-3-bromoindazole,phenyl benzoxazole, methyl naphthoxazole, various aryl benzothiazoles);quinine salts (bisulfate, sulfate, chloride, oleate, and tannate);quinoline derivatives (8-hydroxyquinoline salts, 2-phenylquinoline);hydroxy- or methoxy-substituted benzophenones; uric and violuric acids;tannic acid and its derivatives (e.g., hexaethylether); (butyl carbotol)(6-propyl piperonyl)ether; hydroquinone; benzophenones (oxybenzene,sulisobenzone, dioxybenzone, benzoresorcinol,2,2′,4,4′-tetrahydroxybenzophenone,2,2′-dihydroxy-4,4′-dimethoxybenzophenone, octabenzone;4-isopropyldibenzoylmethane; butylmethoxydibenzoylmethane; etocrylene;octocrylene; [3-(4′-methylbenzylidene boman-2-one) and4-isopropyl-di-benzoylmethane, and any combination thereof.

Representative examples of sunless tanning agents usable in the presentinvention include, without limitation, dihydroxyacetone, glyceraldehyde,indoles and their derivatives. The sunless tanning agents can be used incombination with the sunscreen agents.

The term “antibiotic agent” as used herein means any of a group ofchemical substances having the capacity to inhibit the growth of, or todestroy bacteria, and other microorganisms, used chiefly in thetreatment of infectious diseases. Examples of antibiotic agents include,but are not limited to, Penicillin G; Methicillin; Nafcillin; Oxacillin;Cloxacillin; Dicloxacillin; Ampicillin; Amoxicillin; Ticarcillin;Carbenicillin; Mezlocillin; Azlocillin; Piperacillin; Imipenem;Aztreonam; Cephalothin; Cefaclor; Cefoxitin; Cefuroxime; Cefonicid;Cefmetazole; Cefotetan; Cefprozil; Loracarbef; Cefetamet; Cefoperazone;Cefotaxime; Ceftizoxime; Ceftriaxone; Ceftazidime; Cefepime; Cefixime;Cefpodoxime; Cefsulodin; Fleroxacin; Nalidixic acid; Norfloxacin;Ciprofloxacin; Ofloxacin; Enoxacin; Lomefloxacin; Cinoxacin;Doxycycline; Minocycline; Tetracycline; Amikacin; Gentamicin; Kanamycin;Netilmicin; Tobramycin; Streptomycin; Azithromycin; Clarithromycin;Erythromycin; Erythromycin estolate; Erythromycin ethyl succinate;Erythromycin glucoheptonate; Erythromycin lactobionate; Erythromycinstearate; Vancomycin; Teicoplanin; Chloramphenicol; Clindamycin;Trimethoprim; Sulfamethoxazole; Nitrofurantoin; Rifampin; Mupirocin;Metronidazole; Cephalexin; Roxithromycin; Co-amoxiclavuanate;combinations of Piperacillin and Tazobactam; and their various salts,acids, bases, and other derivatives. Anti-bacterial antibiotic agentsinclude, but are not limited to, penicillins, cephalosporins,carbacephems, cephamycins, carbapenems, monobactams, aminoglycosides,glycopeptides, quinolones, tetracyclines, macrolides, andfluoroquinolones.

The term “anti-fungal agent” as used herein means any of a group ofchemical substances having the capacity to inhibit the growth of or todestroy fungi. Anti-fungal agents include but are not limited toAmphotericin B, Candicidin, Dermostatin, Filipin, Fungichromin,Hachimycin, Hamycin, Lucensomycin, Mepartricin, Natamycin, Nystatin,Pecilocin, Perimycin, Azaserine, Griseofulvin, Oligomycins, Neomycin,PyrroInitrin, Siccanin, Tubercidin, Viridin, Butenafine, Naftifine,Terbinafine, Bifonazole, Butoconazole, Chlordantoin, Chlormidazole,Cloconazole, Clotrimazole, Econazole, Enilconazole, Fenticonazole,Flutrimazole, Isoconazole, Ketoconazole, Lanoconazole, Miconazole,Omoconazole, Oxiconazole, Sertaconazole, Sulconazole, Tioconazole,Tolciclate, Tolindate, Tolnaftate, Fluconawle, Itraconazole,Saperconazole, Terconazole, Acrisorcin, Amorolfine, Biphenamine,Bromosalicylchloranilide, Buclosamide, Calcium Propionate,Chlorphenesin, Ciclopirox, Cloxyquin, Coparaffinate, Diamthazole,Exalamide, Flucytosine, Halethazole, Hexetidine, Loflucarban, Nifuratel,Potassium Iodide, Propionic Acid, Pyrithione, Salicylanilide, SodiumPropionate, Sulbentine, Tenonitrozole, Triacetin, Ujothion, UndecylenicAcid, and Zinc Propionate.

The term “anti-viral agent” as used herein means any of a group ofchemical substances having the capacity to inhibit the replication of orto destroy viruses used chiefly in the treatment of viral diseases.Anti-viral agents include, but are not limited to, Acyclovir, Cidofovir,Cytarabine, Dideoxyadenosine, Didanosine, Edoxudine, Famciclovir,Floxuridine, Ganciclovir, Idoxuridine, Inosine Pranobex, Lamivudine,MADU, Penciclovir, Sorivudine, Stavudine, Trifluridine, Valacyclovir,Vidarabine, Zalcitabine, Zidovudine, Acemannan, Acetylleucine,Amantadine, Amidinomycin, Delavirdine, Foscamet, Indinavir, Interferons(e.g., IFN-alpha), Kethoxal, Lysozyme, Methisazone, Moroxydine,Nevirapine, Podophyllotoxin, Ribavirin, Rimantadine, Ritonavir2,Saquinavir, Stailimycin, Statolon, Tromantadine, Zidovudine (AZT) andXenazoic Acid.

The term “anti-protozoal agent” as used herein means any of a group ofchemical substances having the capacity to inhibit the growth of or todestroy protozoans used chiefly in the treatment of protozoal diseases.Examples of antiprotozoal agents, without limitation includepyrimethamine (Daraprim®) sulfadiazine, and Leucovorin.

Examples of anti-acne agents include, without limitation, keratolytics,such as salicylic acid, sulfur, glycolic, pyruvic acid, resorcinol, andN-acetylcysteine; and retinoids such as retinoic acid and itsderivatives (e.g., cis and trans, esters).

“Anesthetic agents” refers to agents that result in a reduction or lossof sensation. Non-limiting examples of anesthetic drugs that aresuitable for use in the context of the present invention includepharmaceutically acceptable salts of lidocaine, bupivacaine,chloroprocaine, dibucaine, etidocaine, mepivacaine, tetracaine,dyclonine, hexylcaine, procaine, cocaine, ketamine, pramoxine andphenol.

“Steroidal anti-inflammatory agent”, as used herein, refer to any one ofnumerous compounds containing a 17-carbon 4-ring system and includes thesterols, various hormones (as anabolic steroids), and glycosides.Representative examples of steroidal anti-inflammatory drugs include,without limitation, corticosteroids such as hydrocortisone,hydroxyltriamcinolone, alpha-methyl dexamethasone,dexamethasone-phosphate, beclomethasone dipropionates, clobetasolvalerate, desonide, desoxymethasone, desoxycorticosterone acetate,dexamethasone, dichlorisone, diflorasone diacetate, diflucortolonevalerate, fluadrenolone, fluclorolone acetonide, fludrocortisone,flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortinebutylesters, fluocortolone, fluprednidene (fluprednylidene) acetate,flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisonebutyrate, methylprednisolone, triamcinolone acetonide, cortisone,cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,fluradrenolone, fludrocortisone, difluorosone diacetate, fluradrenoloneacetonide, medrysone, amcinafel, amcinafide, betamethasone and thebalance of its esters, chloroprednisone, chlorprednisone acetate,clocortelone, clescinolone, dichlorisone, diflurprednate, flucloronide,flunisolide, fluoromethalone, fluperolone, fluprednisolone,hydrocortisone valerate, hydrocortisone cyclopentylpropionate,hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone,beclomethasone dipropionate, triamcinolone, and mixtures thereof.

“Non-steroidal anti-inflammatory agents” refers to a large group ofagents that are aspirin-like in their action, including ibuprofen(Advil)®, naproxen sodium (Aleve)®, and acetaminophen (Tylenol)®.Additional examples of non-steroidal anti-inflammatory agents that areusable in the context of the present invention include, withoutlimitation, oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam,and CP-14,304; disalcid, benorylate, trilisate, safapryn, solprin,diflunisal, and fendosal; acetic acid derivatives, such as diclofenac,fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac,tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac,oxepinac, felbinac, and ketorolac; fenamates, such as mefenamic,meclofenamic, flufenamic, niflumic, and tolfenamic acids; propionic acidderivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen,ketoprofen, fenoprofen, fenbufen, indopropfen, pirprofen, carprofen,oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen,and tiaprofenic; pyrazoles, such as phenylbutazone, oxyphenbutazone,feprazone, azapropazone, and trimethazone. Mixtures of thesenon-steroidal anti-inflammatory agents may also be employed, as well asthe dermatologically acceptable salts and esters of these agents. Forexample, etofenamate, a flufenamic acid derivative, is particularlyuseful for topical application.

“Antipruritic agents” as used herein refers to those substances thatreduce, eliminate or prevent itching. Suitable antipruritic agentsinclude, without limitation, pharmaceutically acceptable salts ofmethdilazine and trimeprazine.

“An anti-oxidant agent” as used herein refers to a substance thatinhibits oxidation or reactions promoted by oxygen or peroxides.Non-limiting examples of anti-oxidants that are usable in the context ofthe present invention include ascorbic acid (vitamin C) and its salts,ascorbyl esters of fatty acids, ascorbic acid derivatives (e.g.,magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbylsorbate), tocopherol (vitamin E), tocopherol sorbate, tocopherolacetate, other esters of tocopherol, butylated hydroxy benzoic acids andtheir salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid(commercially available under the tradename TroloxR), gallic acid andits alkyl esters, especially propyl gallate, uric acid and its salts andalkyl esters, sorbic acid and its salts, lipoic acid, amines (e.g.,N,N-diethylhydroxylamine, amino-guanidine), sulfhydryl compounds (e.g.,glutathione), dihydroxy fumaric acid and its salts, glycine pidolate,arginine pilolate, nordihydroguaiaretic acid, bioflavonoids, curcumin,lysine, methionine, proline, superoxide dismutase, silymarin, teaextracts, grape skin/seed extracts, melanin, and rosemary extracts.

“Chemotherapeutic agent” refers to chemicals useful in the treatment orcontrol of a disease. Non-limiting examples of chemotherapeutic agentsusable in context of the present invention include daunorubicin,doxorubicin, idarubicin, amrubicin, pirarubicin, epirubicin,mitoxantrone, etoposide, teniposide, vinblastine, vincristine, mitomycinC, 5-FU, paclitaxel, docetaxel, actinomycin D, colchicine, topotecan,irinotecan, gemcitabine cyclosporin, verapamil, valspodor, probenecid,MK571, GF120918, LY335979, biricodar, terfenadine, quinidine,pervilleine A and XR9576.

“Antihistamine agent” as used herein refers to any of various compoundsthat counteract histamine in the body and that are used for treatingallergic reactions (such as hay fever) and cold symptoms. Non-limitingexamples of antihistamines usable in context of the present inventioninclude chlorpheniramine, brompheniramine, dexchlorpheniramine,tripolidine, clemastine, diphenhydramine, promethazine, piperazines,piperidines, astemizole, loratadine and terfenadine.

“Vitamin” as used herein, refers to any of various organic substancesessential in minute quantities to the nutrition of most animals;vitamins act especially as coenzymes and precursors of coenzymes in theregulation of metabolic processes. Non-limiting examples of vitaminsusable in context of the present invention include vitamin A and itsanalogs and derivatives: retinol, retinal, retinyl palmitate, retinoicacid, tretinoin, iso-tretinoin (known collectively as retinoids),vitamin E (tocopherol and its derivatives), vitamin C (L-ascorbic acidand its esters and other derivatives), vitamin B₃ (niacinamide and itsderivatives), alpha hydroxy acids (such as glycolic acid, lactic acid,tartaric acid, malic acid, citric acid, etc.) and beta hydroxy acids(such as salicylic acid and the like).

“Hormone” as used herein refers to natural substances produced by organsof the body that travel by blood to trigger activity in other locationsor their synthetic analogs. Suitable hormones for use in the context ofthe present invention include, but are not limited to, calciferol(Vitamin D3) and its products, androgens, estrogens and progesterones.

“Anti-dandruff agents” as used herein refer to agents that reduce,eliminate or prevent a scurf from forming on skin, especially of thescalp, that comes off in small white or grayish scales. Exemplaryanti-dandruff ingredients usable in context of the present inventioninclude, without limitation, zinc pyrithione, shale oil and derivativesthereof such as sulfonated shale oil, selenium sulfide, sulfur;salicylic acid, coal tar, povidone-iodine, imidazoles such asketoconazole, dichlorophenyl imidazolodioxalan, clotrimazole,itraconazole, miconazole, climbazole, tioconazole, sulconazole,butoconazole, fluconazole, miconazolenitrite and any possible stereoisomers and derivatives thereof such as anthralin, piroctone olamine(Octopirox), selenium sulfide, and ciclopiroxolamine, and mixturesthereof.

“Anti-skin atrophy actives” refers to substances effective inreplenishing or rejuvenating the epidermal layer by promoting ormaintaining the natural process of desquamation. Examples of antiwrinkleand antiskin atrophy actives which can be used in context of the presentinvention include retinoic acid, its prodrugs and its derivatives (e.g.,cis and trans) and analogues; salicylic acid and derivatives thereof,sulfur-containing D and L amino acids and their derivatives and salts,particularly the N-acetyl derivatives, a preferred example of which isN-acetyl L-cysteine; thiols, e.g. ethane thiol; alpha-hydroxy acids,e.g. glycolic acid, and lactic acid; phytic acid, lipoic acid;lysophosphatidic acid, and skin peel agents (e.g., phenol and the like).Sclerosing agents or sclerosants may be also employed. A “sclerosant”refers to an agent used as a chemical irritant injected into a vein insclerotherapy. The most common ones are morrhuate sodium, sodiumtetradecyl sulfate, laureth 9 and ethanolamine oleate.

Cleansing agents which may be used in the present invention includesurfactant based cleansing agents, examples of which have been listedhereinabove. Other non-surfactant-based cleansing agents known to thoseof skill in the art may also be employed.

“Caustic agents” refer to substances capable of destroying or eatingaway epithelial tissue by chemical action. Caustic agents can be used toremove dead skin cells. For example, beta-hydroxy acids, naturallyderived acids with a strong kerolytic effect, are useful for problemskin, acne or peeling.

“Hypopigmenting agents” refer to substances capable of depigmenting theskin. Suitable hypopigmenting agents include hydroquinones, mequinol,and various protease inhibitors including serine protease inhibitors,active soy and retinoic acid.

The topical compositions of the present invention can be applied locallyto the skin and may be in any form including solutions, oils, creams,ointments, gels, lotions, shampoos, milks, cleansers, moisturizers,sprays, skin patches and the like.

In another embodiment, a compound of the present invention, a carrierand, optionally, additional active ingredients are formed into acomposition comprising a solution, emulsion or gel suspension.

In some embodiments, a compound of the present invention, apharmaceutical or cosmetic carrier and, optionally, one or moreadditional active ingredients are in the form of a solution. A solutioncan be prepared by mixing a solute or dissolved substance (such as acompound of the invention and, optionally, one or more activeingredient(s)) uniformly throughout a solvent carrier such as water ororganic solvents, such as the alcohols (e.g. ethanol or isopropanol,acetone).

In another embodiment, a composition comprising a compound of thepresent invention, a carrier and other, optional ingredients can bedispersed in an emulsion. An emulsion is a two-phase system prepared bycombining two immiscible liquid carriers, one of which is disburseduniformly throughout the other and consists of globules that havediameters equal to or greater than those of the largest colloidalparticles. The globule size is critical and must be such that the systemachieves maximum stability. Usually, separation of the two phases willnot occur unless a third substance, an emulsifying agent, isincorporated. Thus, a basic emulsion contains at least three components,the two immiscible liquid carriers and the emulsifying agent as well asthe compound of the invention. Most emulsions incorporate an aqueousphase into a non-aqueous phase (or vice versa). However, it is possibleto prepare emulsions that are basically non-aqueous, for example,anionic and cationic surfactants of the non-aqueous immiscible systemglycerin and olive oil.

Emulsifying agent carriers useful in the present invention are describedhereinabove.

When the composition of the invention is an emulsion including acompound of the invention, non-lipid-based vehicles are particularlyuseful due to the lipophilic nature of the compounds.

In another embodiment, a composition containing a compound of thepresent invention can be mixed with a gel suspension, (a semi-solidcarrier) or solid carrier to form a paste, powder, ointment, cream,lotion, hydrogel or the like.

For example, ointments may be prepared which are in gel-suspension form.These are semi-solid preparations intended for external application tothe epithelium. Generally, ointment bases are categorized intohydrocarbon bases (oleaginous), which may use white petroleum as a base;adsorption bases (anhydrous), which may use hydrophilic petroleum oranhydrous lanolin; emulsion bases (water and oil type); emulsion bases(oil and water type); and water soluble bases, which often usepolyethylene glycol as an ointment base.

Additional compositions of the present invention can be readily preparedusing technology which is known in the art such as described inRemington's Pharmaceutical Sciences, 18th or 19th editions, published bythe Mack Publishing Company of Easton, Pa. incorporated herein byreference in its entirety.

In some embodiments, the compositions of the present invention includeabout 0.001% to about 10.0% w/w of a compound of the present invention.

According to another aspect of the present invention, there is provideda method of preparing the compositions described hereinabove. Theprocess generally includes admixing the at least one compound of thepresent invention, as described hereinabove, and the pharmaceutically,cosmetically or cosmeceutically acceptable carrier. In cases whereadditional active ingredients, as detailed above, are present in thecompositions, the process includes admixing these ingredients togetherwith the active ingredients and the carrier. The mixing techniqueutilized in the process of the present invention can involve any one ofthe known techniques for formulating topical compositions. A variety ofexemplary formulation techniques that are usable in the process of thepresent invention is described, for example, in Harry's Cosmeticology,Seventh Edition, Edited by J B Wilkinson and R J Moore, LongmannScientific & Technical, 1982, incorporated herein by reference in itsentirety.

According to another aspect of the present invention, there is provideda method of treating a medical, cosmetic and/or cosmeceutical conditionassociated with epithelial tissues that comprises hair loss. The methodis effected by topically applying, a pharmaceutically, cosmetically orcosmeceutically effective amount of the composition of the presentinvention as described above onto a surface.

As used herein the terms “pharmaceutically effective amount”,“cosmetically effective amount”, or “cosmeceutically effective amount”refer to the amount of any of the compositions of the invention thatresult in a therapeutic or beneficial effect following itsadministration to a subject. The pharmaceutical, cosmeceutical, orcosmetic effect can be curing, minimizing, preventing or ameliorating adisease or disorder, improving the physical appearance and aesthetics,or may have any other pharmaceutical, cosmeceutical or cosmeticbeneficial effect. The concentration of the substance is selected so asto exert its pharmaceutical, cosmeceutical or cosmetic effect, but lowenough to avoid significant side effects within the scope and soundjudgment of the skilled artisan. The effective amount of the compositionmay vary with the particular epithelial tissue being treated, the ageand physical condition of the biological subject being treated, theseverity of the condition, the duration of the treatment, the nature ofconcurrent therapy, the specific compound, composition or other activeingredient employed, the particular carrier utilized, and like factors.

A skilled artisan can determine a pharmaceutically effective amount ofthe inventive compositions by determining the unit dose. As used herein,a “unit dose” refers to the amount of inventive composition required toproduce a response of 50% of maximal effect (i.e. ED₅₀). The unit dosecan be assessed by extrapolating from dose-response curves derived fromin vitro or animal model test systems.

According to some embodiments of the present invention, the compositionsof the present invention are applied topically as needed. According tosome embodiments, the inventive compositions are topically appliedbetween one and four times a day. According to some embodiments, theinventive compositions are topically applied twice a day (e.g., once inthe morning and once in the evening). According to some suchembodiments, the topical application of the compositions of the presentinvention is carried out daily. Some conditions may require topicalapplication for an indeterminate length of time.

In one embodiment, the inventive compositions are topically administeredto the epithelial surface of a subject. Non limiting examples ofepithelial surfaces onto which the compositions of the present inventioncan be applied topically include the lateral aspect of forearms, thelateral aspect of legs, elbows, feet, backhands, back, scalp, face,eyebrows, eyelids, lip, and any other skin surfaces, and any mucosalmembrane described herein.

Alternatively, the compositions may be administered to the epithelialcondition as a component of, for example, a bandage, adhesive, ortransdermal patch. In these instances, the compositions may be anintegral component of the bandage, adhesive, or transdermal patch andare thereby applied to the epithelial surface.

As used herein the term “treating” includes abrogating, substantiallyinhibiting, slowing or reversing the progression of a condition,substantially ameliorating clinical or aesthetical symptoms of acondition, substantially preventing the appearance of clinical oraesthetical symptoms of a condition, protecting from harmful or annoyingstimuli or generally promoting healthy epithelial tissue.

The term “condition” includes a variety of conditions related to skin ormucosal membranes. This term is meant to include disorders or diseases,the promotion of healthy epithelium; dry skin; and inflammation causedby any underlying mechanism or disorder.

In some embodiments, the compositions of the invention are administeredto treat a skin condition that is already present, such as, but notlimited to, alopecia.

The topical therapeutic compositions may be formulated as ophthalmicpreparations to treat alopecia of the eyelashes and alopecia of theeyebrows. Ophthalmic preparations for topical administration can include(pharmaceutical) carriers such as sterile and non-sterile aqueoussolutions, non-aqueous solutions in common solvents such as alcohols, orsolutions comprising a compound of Formula I in liquid or solid oilbases. Such preparations can be prepared readily using technology knownin the art, for example, as described in “The Art, Science andTechnology of Pharmaceutical Compounding,” Second Edition, edited byLoyd V. Allen, Jr., Ph.D., and published by the American PharmaceuticalAssociation of Washington D.C., and in “Remington's PharmaceuticalSciences,” 18th or 19th Editions, published by the Mack PublishingCompany of Easton, Pa. In preparing an ophthalmic product, a skilledartisan will take into consideration a number of general considerations,including sterility, buffer capacity and pH, tonicity, viscosity,stability, additives, particle size, packaging and preservatives.

Sterile isotonic solutions, properly preserved, are suitable forpreparing ophthalmic solutions. In most cases, when the concentration ofthe active ingredient is low, i.e., less than about 2.5% to about 3.0%,the active ingredient can be dissolved directly in the isotonic vehicle.In some embodiments, compatible excipients, such as preservatives,antioxidants and viscosity enhancers, may be added. For comfort duringadministration, ophthalmic and nasal solution dosage forms must be“isotonic” with body fluids.

Ophthalmic suspensions are dispersions of finely divided, relativelyinsoluble ingredients in an aqueous vehicle containing suitablesuspending and dispersing agents. Dosage uniformity often requires briskshaking of the suspension to distribute the suspended substance. Thesize of particles in an ophthalmic suspension must be micronized so thatthe particles are small enough to not irritate the eye.

Ophthalmic ointments offer the advantage of longer contact time andgreater total bioavailability. The amount of solid released in unit timeis a function of concentration, solubility in the ointment base, anddiffusivity of the substance in the base. Ophthalmic ointments areprepared so that they do not irritate the eye, do permit diffusion ofthe active ingredient, and do retain the activity of the activeingredient for a reasonable period of time when stored properly. Whitepetrolatum is the base primarily used for ophthalmic ointments. Powdersincorporated in the preparation must be micronized and sterilized toensure that the final product is nongritty and thus nonirritating.

The present invention described hereinabove has both human andveterinary utility. The term “subject” as used herein includes animalsof mammalian origin. The present invention has utility in humansubjects.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range is encompassed within the invention. The upper and lowerlimits of these smaller ranges which may independently be included inthe smaller ranges is also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either bothof those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describedthe methods and/or materials in connection with which the publicationsare cited.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “and”, and “the” include plural references unlessthe context clearly dictates otherwise. All technical and scientificterms used herein have the same meaning.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present invention, and are not intended to limit thescope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Centigrade,and pressure is at or near atmospheric.

Compositions of the present invention can be prepared readily usingtechnology which is known in the art such as described in Remington'sPharmaceutical Sciences, 18th or 19th editions, published by the MackPublishing Company of Easton, Pa., which is incorporated herein byreference.

Example 1 Bovine Cornea Hydrolysis Assay

The cellular effects of PGF_(2α) in vivo are mediated by a Gprotein-coupled transmembrane receptor designated the FP receptor (O,Saito et al, Am J. Physiol. Renal Physiol. 284(6): F1164-70 (2003)).Woodward et al used an isolated feline iris sphincter, where prostanoidFP receptors and prostamide receptors coexist, as a test system to showthat prostaglandin-ethanolamides (prostamides) produce their effects byinteracting with receptive targets distinct from prostaglandin receptors(David F. Woodward, et al., “Identification of an Antagonist ThatSelectively Blocks the Activity of Prostamides(Prostaglandin-Ethanolamides) in the Feline Iris,” Br. J. Pharmacol.150(3): 352-52 (2007)).

A bovine cornea hydrolysis test system (K. M. Maxey, et al., “TheHydrolysis of Bimatoprost in Coeal Tissue Generates a PotentialProstanoid FP Receptor Agonist,” Survey of Opthalmology, 47 (Suppl 1):S34-40 (2002)) has been used to determine whether four test compounds ofthe present invention, namely 16-phenoxy PGF_(2α) cyclopropyl amide;17-phenyl trinor PGF_(2α) cyclopropyl amide; 16-phenoxy PGF_(2α)cyclopropyl methyl amide; and 17-phenyl trinor PGF_(2α) cyclopropylmethyl amide, react similarly to bimatoprost in this test system.

Method

Bovine corneas are excised within 1-2 hour of death. For each compoundtested, one cornea (0.6 g) is placed into an 18 mm×150 mm glass testtube containing 10 ml of phosphate-buffered saline (“PBS”) at pH 7.4.The compound of interest (250 μg in about 120 μl ethanol) is added toeach test tube containing a cornea and to a tube containing only 10 mlof PBS (no cornea), which served as a negative control. Test tubes arecovered with parafilm and incubated at 37° C. with shaking.

After the first time point, a 5 ml aliquot is removed from each testtube and transferred into another marked test tube. The remainingmaterial continues to incubate at 37° C. until subsequent test timepoint(s) is/are reached. For each test tube, one ml of 5% KHSO₄ is addedto bring the pH down to about 3 and sufficient NaCl is added to saturatethe solution, the solution then is extracted three times with 80% ethylacetate-hexane. The solvent is evaporated under nitrogen, dissolved in200 μl of 80% ethyl acetate-hexane, and the 200 μl sample thentransferred to a 2 ml screw cap vial. Samples are stored at −20° C.until run on an HPLC column.

After the second time point, the cornea is removed from eachexperimental test tube. For each test tube, one ml of 5% KHSO₄ is addedto bring the pH down to about 3 and sufficient NaCl added to saturatethe solution; the solution then is extracted three times with 80% ethylacetate-hexane. The solvent is evaporated under nitrogen, dissolved in200 μl of 80% ethyl acetate-hexane, and the 200 μl sample thentransferred to 2 ml screw cap vials. Samples are stored at −20° C. untilthey are run on an HPLC column.

For HPLC, samples are run on a Beckman Ultrasphere ODS analytical C18HPLC column (5μ, 4.6 mm×25 cm) at 1 ml/min using either 60:40:0.1 or70:30:0.1 methanol: water:acetic acid as solvent. Absorbance ismonitored at 210 nm.

Results

Hydrolysis data for four test compounds of the present invention, namely16-phenoxy PGF_(2α) cyclopropyl amide; 17-phenyl trinor PGF_(2α)cyclopropyl amide; 16-phenoxy PGF_(2α) cyclopropyl methyl amide; and17-phenyl trinor PGF_(2α) cyclopropyl methyl amide, are shown in Table1.

TABLE 1 bovine cornea hydrolysis Compound % Hydrolyzed after 12 hr17-phenyl trinor PGF_(2α) 0 cyclopropyl methyl amide (negative control)17-phenyl trinor PGF_(2α) 1.1 cyclopropyl methyl amide (cornea sample 1)17-phenyl trinor PGF_(2α) 0.83 cyclopropyl methyl amide (cornea sample2) 17-phenyl trinor PGF_(2α) 0.8 cyclopropyl methyl amide (cornea sample3) Avg 0.91% 16-phenoxy PGF_(2α) 0 cyclopropyl amide (negative control)16-phenoxy PGF_(2α) 2.0 cyclopropyl amide (cornea sample 1) 16-phenoxyPGF_(2α) 1.89 cyclopropyl amide (cornea sample 2) 16-phenoxy PGF_(2α)1.44 cyclopropyl amide (cornea sample 3) Avg 1.78% 17-phenyl trinorPGF_(2α) 0 cyclopropyl amide (negative control) 17-phenyl trinorPGF_(2α) 1.31 cyclopropyl amide (cornea sample 1) 17-phenyl trinorPGF_(2α) 2.0 cyclopropyl amide (cornea sample 2) 17-phenyl trinorPGF_(2α) 2.15 cyclopropyl amide (corneal sample 3) Avg 1.82% 16-phenoxyPGF_(2α) 0 cyclopropyl methyl amide (negative control) 16-phenoxyPGF_(2α) 1.28 cyclopropyl methyl amide (cornea sample 1) 16-phenoxyPGF_(2α) 1.18 cyclopropyl methyl amide (cornea sample 2) 16-phenoxyPGF_(2α) 1.2 cyclopropyl methyl amide (cornea sample 3) Avg 1.22%

Conclusion

It appears that the HPLC profiles resulting from the hydrolysisexperiments for these four test compounds are different from the profilepublished for bimatoprost.

Example 2 Use for Restoring Eyelashes

In one embodiment, the composition of the present invention is atransparent gel formulated according to Table 2. The formulationcomprises water, at least one prostaglandin analog according to thepresent invention (concentration about 0.001% to about 0.05% w/w of thecomposition); a thickener, optionally a hair stimulating agent;caffeine, and at least one penetrating agent and the pH adjusted to 7.2.The gel is applied as a fine line at the skin-eyelash border every nighton clean dry eyes. The gel is aqueous enough to spread to the hairfollicles but thick enough not to drip.

TABLE 2 Transparent Gel Formulation I Range (expressed as Ingredientpercent by weight) Water   50-99.95 Pentylene glycol  2.00-20.00 Ethanol 0.1-15.00 Propylene glycol alginate 0.23-3.00 Acrylates/C10-30 Alkylacrylate crosspolymer 0.10-1.00 Butyl glycol  0.50-10.00 Caffeine0.05-4.00 Oleanolic Acid 0.001-0.1  PPG-26-Buteth-26 0.001-1.0 Propylene glycol 0.1-10  Apigenin 0.001-0.1  Biotinoyl tripeptide-10.00001-0.1   Tetrahydroxypropyl Ethylene diamine  0.1-2.00 Cyclopropyl7-(3,5-dihydroxy-2-(3-hydroxy-4- 0.001-5.00 phenoxy-but-1-enyl)-cyclopentyl)-hept-5- enamide Tetrasodium EDTA0.01-0.25 Disodium phosphate 0.001-1.00  Sodium Phosphate 0.001-1.00 Diazolidinyl Urea 0.05-0.30 Methylparaben 0.05-0.70 Propylparaben0.01-0.70

In another embodiment, the composition is a transparent gel formulatedto comprise at least one of 16-phenoxy PGF_(2α) cyclopropyl amide;17-phenyl trinor PGF_(2α) cyclopropyl amide; 16-phenoxy PGF_(2α)cyclopropyl methyl amide; or 17-phenyl trinor PGF_(2α) cyclopropylmethyl amide (concentration about 0.001% to about 0.05% w/w of thecomposition) plus the following ingredients (Table 3):

TABLE 3 Ingredient Percent (by weight) Water 91.0368%   Pentylene glycol  3% Ethanol 0.95% Propylene glycol alginate  0.5% Acrylates/C10-30Alkyl acrylate crosspolymer  0.3% Butyl glycol  2.0% Caffeine  0.5%Oleanolic Acid 0.001%  PPG-26-Buteth-26 0.01% Propylene glycol 0.56%Apigenin 0.001%  Biotinoyl tripeptide-1 0.0005%  TetrahydroxypropylEthylene diamine  0.5% Cyclopropyl 7-(3,5-dihydroxy-2-(3-hydroxy-4-0.05% phenoxy-but-1-enyl)-cyclopentyl)-hept-5- enamide Tetrasodium EDTA0.05% Disodium phosphate 0.097%  Sodium Phosphate 0.0037%  DiazolidinylUrea  0.3% Methylparaben 0.11% Propylparaben 0.03%

Test formulations contained either 0.025% or 0.05% 16-phenoxy PGF2αcyclopropyl amide. The formulation containing 0.025% 16-phenoxy PGF2αcyclopropyl amide was used on the left side, and the formulationcontaining 0.05% 16-phenoxy PGF2α cyclopropyl amide was used on theright side. Test formulations were given randomly to volunteers withoutconsideration of coloration of eyelashes, race, ethnicity or sex. Unlessotherwise noted there was no significant difference observed for theleft versus the right side.

Subject K. M. was a female age 50 whose original eyelash color waslight. Some thickening was seen within 10 days. Increase in length wasobvious by about 3 weeks. The increase in length was estimated as about55%. The lashes were darker, fuller and showed an upward curving angleof growth.

Subject B. J. H was a female age 42 whose original eyelash color waslight. Eyelashes exhibited obvious growth by week 3. Lashes were muchthicker, fuller, longer and curvier than before use. Increase in lengthwas approximately 80% and the thickness of the lashes approximatelydoubled.

Subject K. Y. was a female age 37 whose original eyelash color was dark.Lashes grew so much that by week 4 the test was discontinued becauseeyelashes were too long. Noticeable results at week 1.

Subject S. V. was a female age 31. By week one, thickness increasednoticeably. By week 4, observed about 50% increase in length of lashes.Lashes appeared darker, fuller, and longer. Lashes improved somewhatafter that but peak result, with some lashes 100% longer, was at 6weeks.

Subject T. D. was a female age 51, whose original eyelash color was darkbut who had poor eyelash length, curve and thickness. Subject noticed animprovement as early as 1 week. By 3 weeks, lashes were 40% longer,thicker and darker and curled upwards. Product continued to improveeyelash condition. After two months, increase in length wasapproximately 55%. Right side was faster to grow.

Subject J. P. was a female, age 59. Eyelashes were visibly darker andthicker within 1 week. Increase in length was noticeable by 2 weeks.Improvement peaked at about 6 weeks with approximately a 45% increase inlength and 60% increase in numbers of eyelashes.

Subject M. M. was a female, age 59. The subject saw general improvementin as little as 1 week. Definite and noticeable improvement by 2 weeks.Estimated increase in length by 4 weeks was 50% Subject thought rightside was better.

Subject R. W. was a female, age 59 with dark eyelashes. Eyelashes weremuch thicker after 2 weeks. Approximately 60% increase in max length at5 weeks.

Subject J. T. was a female, age 38 with light eyelashes. Eyelashesbecame much darker, thicker and approximately 60% longer within 4 weeks.Noticed general improvement in about 2 weeks.

Subject L. H. was a female, age 55 with light eyelashes. Improvement ineyelash quality was noticeable by week 3. By week 5 eyelashes were about100% longer than baseline, darker, and curved upwards.

Subject A. E. was a female, age 42 having a dry eye condition. Thesubject tolerated the product well. Visible results apparent starting asearly as 1 week. At the end of the test (6 weeks), eyelashes were longer(increase 50%), darker, and thicker.

Subject F. P, a female age 48 had worn false eyelashes for long periods.Her lashes were badly damaged and were very short and broken. Subjecthad had Lasik surgery and had dry eye. Subject tolerated the product. Nonoticeable improvement was seen for 2-3 weeks. Suddenly the lashesstarted to get longer, thicker and darker. Final improvement wasapproximately 45% of original length and approximately 60% thicker.

Subject J. M., a male, age 51 had short, dark eyelashes. After 2 weeks,improvement was noticeable. By 4 weeks, lashes were bushy, very thick,dark, and length was increased 50%.

Subject D. T., a female age 31, had very sparse, thin, dark, shorteyelashes. Improvement was noticed by 2 weeks. Final result at 5 weekswas increase in length by approximately 45% in length, 30% increase innumbers, and lashes curled up. Subject thought left side was better.

Subject D. C., an Asian female, age 31, had eyelashes that did notprotrude below the eyelid. After 3-4 weeks, eyelashes had grown to thepoint of clear visibility below lids. Estimate of increase in length 50%thickness 100%, and lashes curled up.

Subject B. R., a male, age 60, had light eyelashes. Product was appliedto one side only. There was a clear difference in sides by 2 weeks.Final increase in length 45%, darker, thicker and lashes curled up.

Subject V. M., a female age 55. Lashes showed noticeable improvement by2 weeks in terms of length, thickness and curve. Also applied toeyebrows which were sparse particularly at ends. Final result was approx60% increase in length and 50% increase in numbers.

Subject G. F., a female, age 55, had short, thin eyelashes. Positiveimprovement seen starting at 2 weeks. Lashes doubled in length (100%)increase, almost 100% thicker, darker, and curled upwards.

Subject S. M., a female age 45, noticed improvement noted by 1 week. Atweek three lashes were 30% longer, thicker and curled. By 6 weeks,length had improved by 50%.

Subject J. Z a female, age 60, showed noticeable improvement by 2 weeks.Final result was increase in length by 45-50%. Lashes were darker andmore upturned.

Subject A. T., a female, age 50, showed improvement after 2 weeks.Noticeable improvement after 4 weeks even without mascara. Subjectthought left side was better.

Example 3 Use for Restoring Eyebrows

A composition prepared according to the present invention is formulatedas a transparent gel as described in the two described embodiments ofExample 2. The formulation comprises water, at least one prostaglandinanalog according to the present invention (concentration about 0.001% toabout 0.05% w/w of the composition); a thickener, optionally a hairstimulating agent; caffeine, and at least one penetrating agent and thepH adjusted to 7.2. The gel is applied by brush as a line at thebrowbone every night on clean, oil-free brows in the absence of makeup.The gel is sufficiently aqueous to spread to the hair follicles butthick enough not to drip.

Test formulations contained either 0.025% or 0.05% 16-phenoxy PGF2αcyclopropyl amide. The formulation containing 0.025% 16-phenoxy PGF2αcyclopropyl amide was used on the left side, and the formulationcontaining 0.05% 16-phenoxy PGF2α cyclopropyl amide was used on theright side. Test formulations were given randomly to volunteers withoutconsideration of coloration of eyelashes, race, ethnicity or sex. Unlessotherwise noted there was no significant difference observed for theleft versus the right side.

Subject K. P.: brows showed a noticeable increase in number of hairs andcolor after 2 weeks.

Subject G. F., a female, age 55. Product was applied to a bald spot inbrow that had been absent for 40 years. Hairs started to fill in.

Example 4 Use for Restoring Scalp Hair

A composition prepared according to the present invention may beformulated as an aerosol spray, a topical cream, ointment or a solution.

An aerosol containing approximately 0.005% to about 5.0% (w/w) of atleast one prostaglandin analog according to the present invention isprepared by dissolving the analog in absolute alcohol. The resultingsolution is filtered and chilled to about minus 30 degrees C. A chilledmixture of dichlorodifluoromethane and dichlorotetrafluoroethane isadded to the solution. Plastic-coated amber bottles are cold filled withthe resulting solution and capped. About 1 cc of the formulation issprayed on the scalp daily at night.

A topical cream is prepared as follows. Tegacid and spermaceti aremelted together at a temperature of about 70 degrees C. to about 80degree C. Methylparaben is dissolved in water and propylene glycol,polysorbate 80, and at least one prostaglandin analog (about 0.005% toabout 5.0% (w/w)) are added in turn, maintaining the temperature atabout 75-80 degrees C. The methylparaben mixture is added slowly to thetegacid and spermaceti melt with constant stirring for at least 30minutes, with additional stirring until the temperature has dropped to40-45° C. Finally, sufficient water is added to bring the final weightto 10000 gm and the preparation is stirred to maintain homogeneity untilcooled and congealed. The formulation is applied nightly.

A topical ointment containing at least one prostaglandin analog (about0.001% to about 5.0% (w/w)) is prepared as follows: White petrolatum andwool fat are melted, strained, and liquid petrolatum added. At least oneprostaglandin analog of the present invention is added; optionally zincoxide and calamine may be added as well. The mixture is milled until thepowders are finely divided and uniformly dispersed. The mixture isstirred into the white petrolatum, melted and cooled with stirring untilthe ointment congeals. The formulation is applied nightly.

Subject B. R., male, age 60: transparent gel formulation from examples 1and 2 was applied to scalp at 1% concentration. Improvement in baldarea, with dark hairs filling in from sides and darkening of certaingray areas, was seen.

Example 5 Use for Restoring Hair Color

A composition prepared according to the present invention is formulatedas an aerosol spray, a topical cream, ointment or a solution. The totalvolume used is about 1 cc per application. The formulation is appliednightly. The concentration of the prostaglandin analog in thecomposition is about 0.001% to about 5.0% (w/w).

Subject B. R., male, age 60: transparent gel formulation from examples 1and 2 was applied to scalp at 1% concentration. Improvement in baldarea, with dark hairs filling in from sides and darkening of certaingray areas, was seen.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theInvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1. A topical composition for treating an epithelial-related condition,comprising: (a) at least one compound of formula XII or a salt offormula XII:

wherein the simple straight line represents a bond lying approximatelyin the surface plane; the wedge shaped bond is directed to the front ofsurface plane; and the hatched bond is directed in the back of thesurface plane; and wherein the compound has optically active isomerswhenever chiral centers are present; and (b) a carrier, whereby thecomposition stimulates hair growth on an epithelial surface to which thecomposition has been applied.
 2. The topical composition according toclaim 1, wherein the at least one compound of formula XII is (16-(3-chlorophenoxy)-17, 18, 19, 20-tetranor PGF₂,) cyclopropyl methylamide.
 3. The topical composition according to claim 1, wherein thecomposition is an ophthalmic composition.
 4. The topical compositionaccording to claim 1, wherein the composition restores pigmentation todepigmented hair.
 5. The topical composition according to claim 1,wherein the epithelial-related condition is alopecia.
 6. The topicalcomposition according to claim 1, wherein the epithelial surface ontowhich the composition is applied topically is an eyelid.
 7. The topicalcomposition according to claim 1, wherein the epithelial-relatedcondition is alopecia of at least one eyelash.
 8. The topicalcomposition according to claim 1, wherein the epithelial surface ontowhich the composition is applied topically is a face.
 9. The topicalcomposition according to claim 1, wherein the condition is alopecia ofat least one eyebrow.
 10. The topical composition according to claim 1,wherein the epithelial surface onto which the composition is appliedtopically is a scalp.
 11. The composition according to claim 1, whereinthe epithelial surface onto which the composition is applied topicallyis above a lip.
 12. The topical composition of claim 1, wherein thecompound of (a) is present in a pharmaceutically effective amount. 13.The topical composition of claim 1, wherein the compound of (a) ispresent in a cosmetically effective amount.
 14. The topical compositionof claim 1, wherein the compound of (a) is present in a cosmeceuticallyeffective amount.